Process for preparing (R)-3-amino-5-methoxychroman

ABSTRACT

A process for preparing (R)-3-amino-5-methoxychroman is provided. The process comprises the steps of (i) dissolving racemic 3-amino-5-methoxychroman and L(+)tartaric acid in water to form the tartrate salt; (ii) heating the solution until a clear solution is obtained; and (iii) crystallizing the tartrate salt by allowing the solution to cool to room temperature.

DESCRIPTION

This application is a divisional of application Ser. No. 08/144,671,filed on Oct. 28, 1993, now U.S. Pat. No. 5,470,151, which is acontinuation-in-part of application Ser. Nos. 07/957,214, filed on Oct.6, 1992 (abandoned), and Ser. No. 07/780,531, filed on Oct. 18, 1991(abandoned). Ser. No. 07/957,214 is a continuation-in-part of Ser. No.07/780,531, which is a continuation-in-part of aplication Ser. No.07/633,247, filed Dec. 21, 1990 (abandoned).

FIELD OF THE INVENTION

The present invention relates to new substituted-3-amino-chromans andthiochromans, enantiomers and salts thereof, processes for theirpreparation, pharmaceutical compositions containing said therapeuticallyactive compounds as well as new intermediates useful in the preparationof the therapeutically active compounds and to the use of said activecompounds in therapy.

An object of the invention is to provide compounds for therapeutic use,especially compounds having a therapeutic activity via the centralnervous system (CNS). A further object is to provide compounds having aselective effect on the 5-hydroxy-tryptamine receptors in mammalsincluding man.

It is also an object of the invention to provide a compound with atherapeutic effect after oral administration.

PRIOR ART

Therapeutically useful 3-amino-dihydro-[1]-benzopyran and benzothiopyranhaving effect on 5-hydroxytryptamine-responsive neurons in mammals aredisclosed in EP 0222 996 and U.S. Pat. No. 4,801,605.

These compounds are defined by the formula ##STR1## wherein Z is 0 or S;

R is hydrogen or lower alkyl;

R₁ is hydrogen, lower alkyl or aryl-lower alkyl;

R₂ is hydrogen, lower alkyl or aryl-lower alkyl; or R₁ and R₂ togetherform a ring with 4-6 carbon atoms;

R₃ is hydrogen, hydroxy, lower alkoxy, aryl- lower- alkoxy, acyloxy oraryloxy when Z is S and R₃ is hydroxy, lower alkoxy, aryl-lower alkoxy,acyloxy or aryloxy when Z is O and R₃ is in 5- or 8-position when Z isO;

R₄ and R₅ are independently hydrogen, lower alkyl or halogen, and mono-or di-S-oxide thereof when Z is S, and pharmaceutically acceptable saltsthereof.

3-Chromanamine hydrochlorides with two alkyl groups in the aromatic ringhaving central stimulating activities are described in J. Med. Chem. 15,p. 863-65 (1972).

Substituted-3-aminochromans intended for therapeutic use in the centralnervous system are disclosed in patent documents, inter alia, EP 0 222996 and WO 91/09853.

BACKGROUND OF THE INVENTION

Various central nervous system disorders such as depression, anxiety,etc. appear to involve the disturbance of the neurotransmittersnoradrenaline (NA) and 5-hydroxytryptamine (5-HT), the latter also knownas serotonin. The drugs most frequently used in the treatment ofdepression are believed to act by improving the neurotransmission ofeither or both of these physiological agonists. It appears that theenhancement of 5-HT neurotransmission primarily affects the depressedmood and anxiety, whereas the enhancement of noradrenalineneurotransmission affects the retardation symptoms occuring in depressedpatients. The invention concerns compounds which have an effect on 5-HTneurotransmission.

Serotonin, or 5-HT, activity is thought to be involved in many differenttypes of psychiatric disorders. For instance, it is thought that anincrease in 5-HT activity is associated with anxiety, while a decreasein 5-HT release has been associated with depression. Serotonin has inaddition been implicated in such diverse conditions as eating disorders,cardiovascular regulation and sexual behavior.

The 5-HT Receptors

The various effects of serotonin may be related to the fact thatserotonergic neurons stimulate the secretion of severeal other hormones,e.g. cortisol, prolactin, β-endorphin, vasopressin and others. Thesecretion of each of these other hormones appears to be regulated on aspecific basis by several different 5-HT (serotonin) receptor subtypes.With the aid of molecular biology techniques, to date, these receptorshave been classified as 5-HT₁, 5-HT₂, 5-HT₃, and 5-HT₄. The 5-HT₁receptor is further subdivided into the 5-HT_(IA), 5-HT_(IB), 5-HT_(IC)and 5-HT_(ID) subtypes. Each receptor subtype is involved in a differentserotonin function and has different properties.

5-HT-Receptor-Active Agents

The mechanism of action for the drugs generally used today in thetherapy of mental depression is indirect, i.e. they act by blocking there-uptake of the neurotransmitters (NA and/or 5-HT) released from nerveterminals in the central nervous system. These drugs increase theconcentration of the neurotransmitters in the synaptic cleft and hencerestore adequate neurotransmission.

A fundamentally different way of improving the neurotransmission in thecentral nervous system in 5-HT neurons would be to use a direct5-HT-receptor-active agent. In order to minimize side effects, or toeffect a specific type of behavior or serotonin function, a highselectivity for a specific 5-HT receptor subtype would be preferred.Agonists can be used to activate specific receptors.

The object of the present invention is to provide compounds fortherapeutic use, especially for treatment of 5-hydroxytryptaminemediated disorders in the central nervous system, for instance,depression, anxiety, obsessive-compulsive disorder (OCD), anorexia,senile dementia, migraine, stroke, Alzheimer's disease, hypertension,thermoregulatory and sexual disturbances, pain and for treatment ofdisturbances in the cardiovascular system.

DISCLOSURE OF THE INVENTION

The object of the present invention is to obtain new compounds whichhave a high affinity to the 5-hydroxytryptamine receptors in the centralnervous system at the same time as they act as agonists, partialagonists or antagonists on the serotonin receptors. Thus, a group of newcompounds of the formula I of the present invention as well as theenantiomers and salts thereof are useful in therapeutic treatment of5-hydroxytryptamine mediated states and disorders such as depression,anxiety, anorexia, senile dementia, Alzheimer's disease, migraine,thermoregulator and sexual disturbances. Further aspects of theinvention are related to the use of the compounds, enantiomers and saltsthereof in pain control and in modulation of the cardiovascular system.

The invention provides compounds of the formula ##STR2## wherein X is Oor S; ##STR3## p is an integer 0, 1 or 2; R is hydrogen, fluoro or C₁-C₆ alkyl;

R₁ is hydrogen, C₁ -C₆ alkyl or C₂ -C₆ alkenyl;

R₂ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₁ -C₄ alkylaryl wherearyl may contain 1 or 2 heteroatoms selected from N, O or S optionallysubstituted by halogen, CN, CF₃, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or C₁ -C₄alkoxy;

R₁ and R₂ may together form a 5- or 6- membered ring which may contain 1or 2 heteroatoms selected from N, O or S;

R₃ is halogen, CN, CF₃, SO₃ CF₃, N₃, NO₂, C₁ -C₆ alkyl, C₂ -C₆ alkenyl,NH₂, NR₅ R₆, COR₇, 5- or 6-membered aryl which may contain 1 or 2heteroatoms selected from N, O or S and being either (i) optionallysubstituted by one or more substituents independently selected fromhalogen, CN, CF₃, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or C₁ -C₄ alkoxy oreither (ii) fused at two adjacent carbon atoms to an aryl ring, saidaryl ring being optionally substituted by one or more substituentsindependently selected from halogen, CN, CF₃, C₁ -C₆ alkyl, C₂ -C₆alkenyl or C₁ -C₄ alkoxy;

R₄ is hydrogen or halogen;

R₅ is hydrogen, C₁ -C₆ alkyl or C₂ -C₆ alkenyl;

R₆ is C₁ -C₆ alkyl or C₂ -C₆ alkenyl; or

R₅ and R₆ may together form a 5- or 6-membered ring which may contain 1or 2 heteroatoms selected from N, O or S;

R₇ is hydrogen, hydroxy, chloro, bromo, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₁-C₄ alkoxy; NR₈ R₉ or 5- or 6- membered aryl which may contain 1 or 2heteroatoms selected from N, O or S optionally substituted by one ormore of halogen, CN, CF₃, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or C₁ -C₄ alkoxy;

R₈ and R₉ are each independently hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl,5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected fromN, O or S optionally substituted by halogen, CN, CF₃, C₁ -C₆ alkyl, C₂-C₆ alkenyl, C₁ -C₄ alkoxy, or may together form a 5- or 6-membered ringcontaining 1 or 2 heteroatoms selected from N, O or S;

enantiomers or salts thereof.

In a preferred embodiment a further aspect of the invention is apharmaceutical preparation containing as active ingredient a compoundaccording to the formula ##STR4## wherein X is O;

R is hydrogen or C₁ -C₆ alkyl;

R₁ is hydrogen, C₁ -C₆ alkyl or C₂ -C₆ alkenyl;

R₂ is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₁ -C₄ alkylaryl where aryl maycontain 1 or 2 heteroatoms selected from N, O or S optionallysubstituted by halogen, CN, CF₃, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or C₁ -C₄alkoxy; or

R₃ is C₂ -C₆ alkenyl, COR₇, 5- or 6-membered aryl which may contain 1 or2 heteroatoms selected from N, O or S and being either (i) optionallysubstituted by one or more substituents independently selected fromhalogen, CN, CF₃, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or C₁ -C₄ alkoxy oreither (ii) fused at two adjacent carbon atoms to an aryl ring, saidaryl ring being optionally substituted by one or more substituentsindependently selected from halogen, CN, CF₃, C₁ -C₆ alkyl, C₂ -C₆alkenyl or C₁ -C₄ alkoxy;

R₄ is hydrogen or fluorine;

R₇ is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₁ -C₄ alkoxy, NR₈ R₉ or 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O orS optionally substituted by one or more of halogen, CN, CF₃, C₁ -C₆alkyl, C₂ -C₆ alkenyl or C₁ -C₄ alkoxy;

R₈ is hydrogen; and R₉ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, 5- or6- membered aryl which may contain 1 or 2 heteroatoms selected from N, Oor S optionally substituted by halogen, CN, CF₃, C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₁ -C₄ alkoxy or may together form a 5- or 6-membered ringcontaining 1 or 2 heteroatoms selected from N, O or S;

an enantiomer or a pharmaceutically acceptable salt thereof.

A preferred group of therapeutically active compounds of formula I arethose wherein R₁ is hydrogen, n-propyl, or i-propyl; and R₂independently of R₁ is n-propyl or i-propyl. It has been found that incompounds where R₁ and R₂ are not the same and one is i-propyl and theother is n-propyl, that it is the R-enantioner that has the highestaffinity for the 5-HT_(IA) receptor and thus, the R-enantiomer of suchcompounds is preferred.

R is preferably hydrogen or methyl. If R is methyl it is preferably inthe cis configuration.

It is also preferred that R₃ is a carbonyl group COR₇. Among thesegroups are the definition of R₇ is alkyl, aminoalkyl e.g. methyl, ethyl,n-propel, i-propyl, cyclopropyl, n-butyl, i-butyl, t-butyl andcyclobutyl or aryl, aminoaryl e.g. phenyl, thienyl, fluorophenyl andfuranyl. Another preferred group is when R₃ is aryl e.g. phenyl,thienyl, furanyl, or fluorophenyl. Another preferred group is when R₃ isalkenyl e.g., i-propenyl and allyl.

Another preferred group of active compounds are those wherein R₄ isfluorine in the 8-position as well as enantiomers thereof.

Certain embodiments of the invention concern:(R)-3-(N-isopropyl-N-propylamino)-5-N-isopropylcarbamoylchroman;(R)-3-(N-isopropyl-N-propylamino)-5-carbamoylchroman;(R)-8-fluoro-3-(N-isopropyl-N-propylamino)5-carbamoylchroman;(R)-8-fluoro-3-[N-(1-ethyl)propyl-N-n-propylamino]-5-carbamoylchroman;(R)-8-fluoro-3-(N-isopropyl,N-n-propylamino)-4-cis-methyl-5-carbamoylchroman;(R)-8-fluoro-3-(N-cyclopentyl,N-n-propylamino)-5-N-methylcarbamoylchroman; (R)-8-fluoro-3-(N-t-butyl,N-n-propylamino)-5-carbamoylchroman;(R)-8-fluoro-3-(N-neopentyl-N-n-propylamino)-5-N-methylcarbamoylchroman;and(R)-8-fluoro-3-(N-isopropyl-N-n-propylamino)-5-N-ethylcarbamoylchroman.

Compounds of formula I wherein R₃ is CN, COOH, COCl, COBr, N₃, or SO₃CF₃ are new intermediates for preparation of the therapeutically activecompounds of formula I.

Definitions

C₁ -C₆ alkyl in formula I representing straight, branched and cyclicalkyl groups having 1 to 6 carbon atoms, for example methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl,t-pentyl, neo-pentyl, n-hexyl, i-hexyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methylcyclopropyl, ethylcyclopropyl,methylcyclobutyl. Preferred alkyl groups have 1 to 4 carbon atoms.

C₂ -C₆ alkenyl in formula I representing straight or branched carbonatoms chains having 2 to 6 carbon atoms and containing one or two doublebond, for example allyl, propenyl, isopropenyl, butenyl, isobutenyl,pentenyl, isopentenyl. Preferred alkenyl groups have 2 to 4 carbon atomsand one double bond.

C₁ -C₄ alkoxy in formula I representing a straight alkoxy group having 1to 4 carbon atoms, for example methoxy, ethoxy, propoxy or butoxy,preferably methoxy and ethoxy.

C₁ -C₄ alkylaryl where aryl may contain 1 or 2 heteroatoms selected fromN, O or S in the definition of R₂ in formula I representing an arylresidue having 3 to 12 carbon atoms in the aromatic ring and optionally1 or 2 heteroatoms selected from N, O or S in the aromatic ring, bond bya straight or branched alkylen chain having 1 to 4 carbon atoms in thealiphatic chain. The aromatic ring may be substituted by one or more ofnitrile, trifluoromethyl, halogen such as fluoro, chloro, bromo, iodo,C₁ -C₆ alkyl, e.g. methyl, ethyl, propyl, C₂ -C₆ alkenyl e.g. alkyl,propenyl, or C₁ -C₄ alkoxy preferably in meta and/or para position.Examples of suitable aryl groups in C₁ -C₄ alkylaryl are phenyl,naphtyl, biphenyl, thienyl, furyl, pyryl, pyrimidyl and pyrridinyl.Preferred C₁ -C₄ alkylaryl groups are unsubstituted and substitutedphenylalkyl groups wherein the alkyl group is a straight or branchedalkyl having 1 to 4 carbon atoms and the aromatic ring may besubstituted by one or more of fluoro, chloro, bromo, iodo, nitrile,trifluoromethyl, methyl or ethyl in meta and/or para position. Forexample benzyl, phenethyl and phenylpropyl, especially preferred isphenylpropyl.

Halogen as used herein represents fluoro, chloro, bromo, iodo,preferably fluoro.

5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected fromN, O or S and being either (i) optionally substituted by one or moresubstituents independently selected from halogen, CN, CF₃, C₁ -C₆ alkyl,C₂ -C₆ alkenyl or C₁ -C₄ alkoxy or either (ii) fused at two adjacentcarbon atoms to an aryl ring, said aryl ring being optionallysubstituted by one or more substituents independently selected fromhalogen, CN, CF₃, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or C₁ -C₄ alkoxy; in thedefinition of R₃ in formula I representing either (i) substituted orunsubstituted phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl,pyradazinyl, thiozolyl, isothiozolyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, piperazinyl or morpholinyl or either (ii) substituted orunsubstituted quinolyl, isoquinolyl, quinazolyl, quinaxazolyl orindolyl.

5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected fromN, O or S in the definition of R₇, R₈ and R₉ in formula I representingphenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,piperazinyl, morpholinyl.

Examples of suitable 5- or 6-membered ring structures formed by R₁ andR₂ or R₅ and R₆, or R₈ and R₉ respectively and the nitrogen atom andwhich may contain a further heteroatom selected from N, O or S arepiperazine, morpholine, pyrrolidine, pyrrole, pyrroline, imidazole,imidazoline, imidazolidine, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine.

The compounds of the invention have one or two assymetric carbon atoms.When R is hydrogen the compounds have an assymetric carbon atom adjacentto the nitrogen atom i.e. C₃ and when R is C₁ -C₆ alkyl the compoundshave an assymetric carbon atom adjacent to the nitrogen atom and anassymetric carbon atom adjacent to the alkyl group i.e. C₄. Thus, thecompounds exist as two or four optical isomers, i.e. enantiomers. Boththe pure enantiomers, racemic mixtures are within the scope of thepresent invention. The therapeutic properties of the compounds may to agreater or lesser degree be ascribed to the racemate or to theenantiomers occurring.

Both organic and inorganic acids can be employed to form non-toxicpharmaceutically acceptable acid addition salts of the compounds of thisinvention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic,hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric,pamoic, ethanedisulfonic, sulfamic, succinic, methylsulphonic,propionic, glycollic, malic, gluconic, pyruvic, phenylacetic,4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic,4-hydroxybenzoic, nicotinic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic,naphtalenesulfonic, ascorbinic, cyclohexylsulfamic, fumaric, maleic andbenzoic acids. These salts are readily prepared by methods known in theart.

Methods of Preparation

The compounds of the formula I may be prepared by the followingprocesses constituting a further aspect of the invention.

a. Converting a compound of formula II ##STR5## wherein Y is a leavinggroup such as trifluoromethane sulfonate (OSO₂ CF₃), halide e.g. Cl orBr, and X, R, R₁, R₂ and R₄ are defined as above by substitution of thegroup Y to a carboxy group COZ, wherein Z is Cl, Br, OH, OR_(p) whereR_(p) is C₁ -C₆ alkyl to formation of a compound of formula I wherein R₃is COZ, (IA).

The compound of formula II can be converted to the compound of formulaIA by the following catalytic cycle. Metal M^(o) should be a zerovalenttransition metal, such as Pd or Ni with ability to undergo oxidativeaddition to aryl-Y-bonds e.g. the aryl-SO₃ CF₃ bonds. M^(o) may begenerated in situ from M^(II). The aryl-CO-M^(II) -Y are formed bytreatment with carbon monoxide (CO). ##STR6## Further reagants are analcohol such as alkanol e.g., methanol, ethanol, an amine base such as atrialkylamine e.g., triethylamine in an inert organic solventpreferentially a polar aprotic solvent such as dimethylformamide (DMF),dimethylsulfoxide (DMSO), aceton, acetonitrile etc. The reaction isnormally performed at a temperature between +40° to +120° C. and at apressure between 100 to 500 KPa. Optionally followed by hydrolyze andtreatment with a thionyl halide e.g., thionylchloride to obtain thecorresponding acid halide derivative.

b. Compound of formula I wherein R₃ is COZ (IA) can also be formed bythe reversed process:

A reaction as the catalytic cycle using a zerovalent transition metalM⁰, such as Pd, or Ni with ability to undergo an oxidation addition toZ-Y, wherein Z is defined Cl, Br, OH or OR_(p) where R_(p) is C₁ -C₆alkyl and Y is a leaving group such as SO₃ CF₃ and halide, treatmentwith carbon monoxide followed by addition of a compound of formula III,wherein X, R, R₁, R₂ and R₄ are as defined under formula I. ##STR7## TheZ-CO-M^(II) -Y can also be formed from Z-COCl directly. The reactionconditions and reagant are the same as described in method a. above.Hydrolyze of suitable carboxylic acid ester forms the free acid, whichcan be converted to its acid halide derivative.

c. Converting a compound of formula II ##STR8## wherein X, R, R₁, R₂ andR₄ are as defined above and Y is a leaving group such as Cl, Br or SO₃CF₃ by treatment with a cyanide reagant such as cupper cyanide (CuCN) toobtain a compound of formula I wherein R₃ is CN. The reaction withcyanide reagant is performed in an inert organic solvent such asdimethylformamide, hexamethylenphosphotriamide etc. at a temperaturebetween 20° to 200° C. preferrably between 50° to 150° C. and at normaltemperature.

d. Amination of a compound of formula IA ##STR9## wherein X, R, R₁, R₂and R₄ are as defined above and Z is Cl, Br, OH or OR_(p) where R_(p) isC₁ -C₆ alkyl. If the compound of formula IA is a carboxylic acid esterit must first be hydrolyzed to form the free acid. The free acid is thentransformed into the amide IC via its acid chloride derivative byreaction of the corresponding amine NR₈ R₉, where R₈ and R₉ are asdefined under formula I, in a nonpolar aprotic solvent e.g. toluene,benzen at reflux temperature between 0° to 100° C.

e. Wittig reaction to formation of a compound of formula I where R₃ is aC₂ -C₆ alkenyl group (IE), ##STR10## A 5-carboxy chroman/thiochromanderivative, where X, R, R₁, R₂ and R₄ are defined as above and R₇ isalkyl defined as above (ID) is converted by using a dipolar reagant suchas alkyltriphenylphosphoniumhalide to formation of a correspondingalkenyl group (IE).

f. Catalytic hydrogenation of a 5-alkene chroman/thiochroman derivativeof formula I wherein R₃ is a C₂ -C₆ alkenyl group by using H₂ /Pd, H₂/Pt or H₂ /Raney Ni to formation of corresponding chroman/thiochromanderivative of formula I wherein R₃ is C₁ -C₆ alkyl (IF).

g. Substitution of a 5-bromo-chroman/thiochroman derivative by treatmentwith an appropriate stannic trialkyl reagant in presence of a zerovalentmetal preferrably palladium (Pd^(o)) to obtain a compound of formula Iwherein R₃ is C₁ -C₆ alkyl, C₁ -C₄ alkenyl or aryl, in presence ofcarbonmonoxide (CO) is formed a compound of formula I wherein R₃ is COR₇wherein R₇ is C₁ -C₆ alkyl, C₂ -C₆ alkylen or aryl.

The substitution may be performed by one of the following ways:##STR11## h. Converting the 5-carboxy chroman/thiochroman derivative offormula I ##STR12## where X, R, R₁, R₂ and R₄ are defined as above and Zis Cl, Br by using R₇ Li wherein R₇ is alkyl, alkenyl or aryl as acuprate reagant to obtain corresponding 5-ketochroman/thiochromanderivative. Suitable R₇ Li used is alkyllithium e.g. CH₃ Li,alkenyllithium e.g. CH₂ CHLi or aryllithium e.g. phenyl-Li. The reactionis performed in an inert organic solvent preferrably a nonpolar aproticsolvent such as ethers e.g. diethyl ether, tetrahydrofuran at atemperature between -50°-+50° C.

i. Hydrolysis of a compound of formula I, wherein R₃ is CN (IB)##STR13## wherein X, R, R₁, R₂ and R₄ are as defined above optionallyfollowed by treatment with a thionyl halide e.g. thionylchloride,thionylbromide to obtain a compound of formula I wherein R₃ is COZ whereZ is OH, Cl or Br.

j. Substitution of a compound of formula I, wherein R₃ is CN (IB)##STR14## wherein X, R, R₁, R₂ and R₄ are defined as above by treat-mentwith an appropriate organometallic reagant preferentially anorganolithium such as R₇ Li or a Gringard reagent such as R₇ Mg halidein an inert organic solvent preferentially a nonpolar aprotic solventsuch as bensen, ethers e.g. diethylether, tetrahydrofuran followed byhydrolysis of the intermediate complex to obtain a compound of formula Iwherein R₃ is COR₇ where R₇ is C₁ -C₆ alkyl, C₂ -C₆ alkenyl or aryl.

k. Hydrogeneration of a 5-alkene thiochroman/chroman derivative offormula I wherein R₃ is a C₂ -C₆ alkenyl group by using H₂ /Pd, H₂ /Ptor H₂ /Raney Ni or potassium azodicarboxylate to formation ofcorresponding thiochroman/chroman derivative of formula I wherein R₃ isC₁ -C₆ alkyl.

l. Converting a compound of the formula (II) ##STR15## wherein Y is aleaving group such as trifluoromethanesulphonate (Tf), phosphonate,halide such as Br or J and R, R₁ and R₂ are defined as above bysubstitution of the group Y to R₃ where R₃ is a C₂ -C₆ alkenyl group(IE).

The compound (II) may be converted to (IE) by reaction with a transitionmetal, such as Pd or Ni with ability to form ligand complex and undergooxidative addition. A suitable alkenyl-substituent can be introduced viaa suitable trialkylalkenylstannane.

Further reagents are an amine such as triethylamine and lithiumsalt e.g.lithium chloride. The reaction is s preferentially carried out in apolar aprotic solvent such as dimethylformamide, dioxane, acetonintrilor dimethylsulfoxide at a temperature between +40° to +120° C.

m. Converting a compound of the formula (II) ##STR16## wherein Y is aleaving group such as trifluoromethanesulphonate (Tf), phosphonate,halide such as Br or J and R, R₁ and R₂ are defined as above bysubstitution of the group Y to 5- or 6-membered aryl (Ar) which maycontain 1 or 2 heteroatoms selected from N, O, or S being eithersubstituted or fused at two adjacent carbon atoms to an aryl ring asdefined above to formation of a compound of formula IF.

The compound (II) may be converted to (IF) by reaction with a transitionmetal, such as Pd or Ni with ability to form ligand complex and undergooxidative addition. A suitable aryl-substituent can be introduced via asuitable trialkylarylstannane or aryl-boric acid reagents.

Further reagents are an amine such as triethylamine and lithiumsalt e.g.lithium chloride. The reaction is preferentially carried out in a polaraprotic solvent such as dimethylformamide, dioxane, acetonitril ordimethylsulfoxide at a temperature between +40° to +120° C.

The following method describes one way of obtaining the intermediate offormula IB ##STR17## wherein R₁, R² and R⁴ are defined as in formula IPharmaceutical Preparations

According to the present invention the compounds of the formula I willnormally be administered orally, rectally or by injection, in the formof pharmaceutical preparations comprising the active ingredient eitheras a free base or a pharmaceutically acceptable non-toxic acid additionsalt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate,sulphate, sulphamate, citrate, tartrate, oxalate and the like in apharmaceutically acceptable dosage form. The dosage form may be a solid,semisolid or liquid preparation and may include suitable excipients,diluents and carriers. Usually the active substance will constitutebetween 0.1 and 99% by weight of the preparation, more specificallybetween 0.5 and 20% by weight for preparations intended for injectionand between 0.2 and 50% by weight for preparations suitable for oraladministration.

To produce pharmaceutical preparations containing a compound of theformula I in the form of dosage units for oral application, the selectedcompound may be mixed with a solid excipient or carrier, e.g, lactose,saccharose, sorbitol, mannitol, starches such as potato starch, cornstarch or amylopectin, cellulose derivatives, a binder such as gelatineor poly-vinylpyrrolidone, and a lubricant such as magnesium stearate,calcium stearate, polyethylene glycol, waxes, paraffin, and the like,and then compressed into tablets. If coated tablets are required, thecores, prepared as described above, may be coated with a concentratedsugar solution which may contain e.g. gum arabic, gelatine, talcum,titanium dioxide, and the like. Alternatively, the table can be coatedwith a polymer known to the man skilled in the art, dissolved in areadily volatile organic solvent or mixture of organic solvents.Dyestuffs may be added to these coatings in order to readily distinguishbetween tablets containing different active substances or differentamounts of the active compounds.

For the preparation of soft gelatine capsules, the active substance maybe admixed with e.g. a vegetable oil or poly-ethylene glycol. Hardgelatine capsules may contain granules of the active substance usingeither the above mentioned excipients for tablets e.g. lactose,saccharose, sorbitol, mannitol, starches (e.g. potato starch, cornstarch or amylopectin), cellulose derivatives or gelatine. Also liquidsor semisolids of the drug can be filled into hard gelatine capsules.

Dosage units for rectal application can be solutions or suspensions orcan be prepared in the form of suppositories comprising the activesubstance in admixture with a neutral fatty base, or gelatine rectalcapsules comprising the active substance in admixture with vegetable oilor paraffin oil.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example solutions containing from about 0.2% to about20% by weight of the active substance herein described, the balancebeing diluents and carriers such as sugar and mixture of ethanol, water,glycerol and propylene glycol. Optionally such liquid preparations maycontain colouring agents, flavouring agents, saccharine andcarboxymethyl-cellulose as a thickening agent or other excipients knownto the man in the art.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance, preferably in a concentration of from about 0.5%to about 10% by weight. These solutions may also contain stabilizingagents and/or buffering agents and may conveniently be provided invarious dosage unit ampoules.

Suitable daily doses of the compounds of the invention in therapeuticaltreatment of humans are about 0.01-100 mg/kg bodyweight at peroraladministration and 0.001-100 mg/kg bodyweight at parenteraladministration.

Pharmacology

Pharmacological Treatment of Depression in Man

Evidence is available that in depressed patients the neurotransmissionin the central nervous system (CNS) may be disturbed. These disturbancesappear to involve the neurotransmitters noradrenaline (NA) and5-hydroxytryptamine (5-HT). The drugs most frequently used in thetreatment of depression are considered to act by improving theneurotransmission of either or both of these physiological agonists.Available data suggest that the enhancement of 5-HT neurotransmissionwill primarily improve the depressed mood and anxiety, whereas theenhancement of noradrenaline neurotransmission will rather improve theretardation symptoms occurring in depressed patients. In recent yearsmany efforts have been made to develop new drugs with high selectivityfor the improvement of the 5-HT neurotransmission in the CNS.

The dominating mechanism of action for the drugs generally used today inthe therapy of mental depression is indirect, i.e. they act by blockingthe reuptake of the neurotransmitters (NA and/or 5-HT) released fromnerve terminals in the CNS, thus, increasing the concentration of thesetransmitters in the synaptic cleft and hence restoring an adequateneurotransmission.

A fundamentally different way to improve the neurotransmission in thecentral 5-HT-neurons would be to use a direct 5-HT-receptor agonist. Inorder to minimize side effects, a high selectivity for this kind ofreceptors would then be preferable.

Selective antagonism of the inhibitory autoreceptors located on thecellbodies of 5-HT-neurons would be another fundamentally different wayto improve the 5-HT neurotransmission.

Surprisingly, we have found that a group of compounds of the formula Ihave selective, direct stimulating or inhibitory effect on a subgroup ofcentral 5-HT receptors. Another observation is that some of thosecompounds have a particularly good oral bioavailability. In order toevaluate the selectivity for the subpopulation of 5-HT receptors, theaffinity for various receptors in rat brain were measured in vitro usingreceptor assays (Ki nM).

In general the compounds of formula I wherein R₄ is a hydrogen areagonists with respect to activity on the 5-HT_(IA) receptor.Additionally we have found that the racemate and surprisingly the(R)-enantiomer of the compound3-(N-isopropyl-N-propylamino)-5-N-isopropylcarbamoylchroman has shownhigh affinity and stereoselective direct stimulatory effect on the5-HT_(IA) receptors in CNS combined with a good bioavailability.Surprisingly, we also have found that when a fluoro substituent replacesthe hydrogen in the 8-position of the ring structure of formula I itseems that the pharmacological profile of the fluoro substitutedcompound is different from the similar compound wherein there ishydrogen in the 8-position. The introduction of a fluoro substitutent inthe 8-position shifts the pharmacological profile from an agonisttowards partial agonist or antagonist for the same subreceptor5-HT_(IA). (R)-8-fluoro-3-(N-isopropyl-N-propylamino)-5-carbamoylchromanis an example of a stereoselective 5-HT_(IA) receptor antagonist.

In Vitro Test: Receptor Binding Assay 5-HT_(IA) binding assay. Cerebralcortex+hippocampus from each rat was dissected and homogenized in 15 mlice-cold 50 mM Tris-HCl buffer, 4.0 mM CaCl₂ and 5.7 mM ascorbic acid,pH 7.5 with an Ultra-Turrax (Janke & Kunkel, Staufen, FRG) for ten s.After centrifugation for 12.5 min at 17,000 rpm (39,800×g in a Beckmancentrifuge with a chilled JA-17 rotor (Beckman, Palo Alto, Calif., USA),the pellets were resuspended in the same buffer and homogenization andcentrifugation repeated. To each pellet 5 ml ice-cold 0.32M sucrose wasadded and homogenized for 5 sec. These samples were kept frozen at -70°C. When used they were diluted with the buffer to 8 mg tissue/ml andhomogenized for 10 sec. The tissue homogenates were incubated for tenminutes at 37° C. and then supplied with 10 μM pargyline followed byreincubation for 10 minutes.

The binding assay followed that described by Peroutka, J. Neurochem. 47,529-540, (1986). The incubation mixture (2 ml) contained ³ H-8-OH-DPAT(0.25 to 8 nM), 5 mg/ml tissue homogenate in 50 mM Tris-HCl buffercontaining 4.0 mM CaCl₂ and 5.7 mM ascorbic acid, pH 7.5. Six differentconcentrations of ³ H-8-OH-DPAT were analyzed. Binding experiments werestarted by the addition of tissue homogenate and followed by incubationat 37° C. for 10 minutes. The incubation mixtures were filtered throughWhatman GF/B glass filters with Brandel Cell Harvester (Gaithersburg,Md., USA). The filters were washed twice with 5 ml ice-cold 50mMTris-HCl buffer, pH 7.5, and counted with 5 ml Ready-solv HP (Beckman)in a Beckman LS 3801 scintillation counter. Non-specific binding wasmeasured by the addition of 10 μM 5-HT to the reaction mixture. Thebinding data was processed by non-linear least squares computer analysis(Munson and Rodbard, Anal. Biochem. 107, 220-239, (1980).

The test results are expressed as K_(i) and are given in nM. Forinstance, 3-dipropylamino-5-acetylchroman has K_(i) 1,0 (nM),3-dipropylamino-5-carbamoylchroman has K_(i) 3,1 (nM),3-dipropylamino-5-N-methylcarbamoylchroman has K_(i) 3,3 (nM),3-dipropylamino-5-(2-thienylcarbonylchroman has K_(i) 1,7 (nM) and(R)-8-fluoro-3-(N-isopropyl-N-propylamino)-5-carbamoylchroman has K_(i)5,4 (nM).

Test of Antagonists

Administration of 5-HT_(IA) agonist to rats reduces 5HT synthesis anddecreases the temperature of the rat. To test for an antagonist youfirst administer the test compound and determine if it has any of theeffects of an agonist. Subsequently, a known agonist is administered todetermine if the antagonist is capable of blocking the effect of theagonist and to what extent. A strong antagonist will block the effectsof the agonist. A compound can function both as a partial agonist andhave some antagonist effect by blocking the binding of another strongerknown agonist, for example 8-OHDPAT, to the 5-HT_(IA) receptor. The samereceptor binding assays and bioavailability assays are used as in thetest for agonist.

Test of Antagonists or Partial Agonists

Administration of a 5-HT_(IA) agonist to rats reduces 5HT synthesis rateand decreases the body temperature of the rat. Screening test for anantagonist or a partial agonist are performed by initial administrationof the test compound and determine if it has any of the effects of anagonist.

Subsequently, a known 5-HT_(IA) agonist (reference 8-OH-DPAT) isadministered to determine if the test compound is capable of blockingthe effects of the known agonist and to what extent. An antagonist willblock all effects of the agonist. A compound can function both as a weakagonist and also have some antagonist effect shown by blocking theeffects of the "reference" agonist to a certain extent. Such a compoundis called an partial agonist.

The same receptor binding assays and bioavailability assays are used for5-HT_(IA) agonists as well as for antagonists and partial agonists.

In Vivo Test: Oral Bioavailability in Dogs

The bioavailability test was performed as described below and gives themean value of 17% for the (R)-enantiomer and 21% for the racemate ofcompound 3-(N-isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchromanbased on plasma level measurements in dogs. Dose-effect studies in ratfollowing subcutaneous versus oral administration further support a highavailability of the compound at the receptor after oral administration.

Method: Assessment for oral bioavailability (systemic availability) wasbased on the plasma area under the curve (AUC) method. An aqueous salinesolution of compound of the invention was administered intravenously(i.v.) and orally (p.o.) to the animals and concentrations of thecompound in plasma measured at numerous timepoints. The dosesadministered were 1 μmol.kg⁻¹ and 10 μmol.kg⁻¹ for intravenous and oraladministration, respectively. AUC was calculated according to thetrapezoidal rule. Determination of the test compound in plasma wasaccomplished by an HPLC method which incorporated electrochemicaldetection.

In Vivo Test: Synthesis of 5-HT

As predicted for a selective 5-HT_(IA) agonist, the synthesis rate of5-HT, measured as a significant decrease of the 5-HTP level in rat brainwas recorded after 0,1 mg/kg following subcutaneous administrations aswell as after 0,2 mg/kg oral administration of the (R)-enantiomer ofcompound3-(N-isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman.

Method: The rate of synthesis of 5-HT in the rat streatum was measuredas the accumulation of 5-HTP during 30 min after inhibition of aromaticL-amino acid decarboxylase by NSD 1015 (decarboxylase inhibitor, 100mg/kg i.p.). The test compound was administered 30 min before the NSD1015. The regions of the brain to be examined were dissected, frozen andstored.

The levels of 5-HTP (5-hydroxytryptophan) was determined by use of highperformance liquid chromatography (HPLC) with electrochemical detectionaccording to the method of Magnusson, Nilsson and Westerlund (1980). Themobile phase was 0,1M phosphate buffer (pH2,5):methanol:acetonitrile-89:9:2 v/v, containing 1 mM octylsulphate.The frozen samples were weighed and homogenized in 0,1M perchloric acid,containing 2,5 nM sodium bisulphite, 1 mM ethylene diamine tetraaceticacid (EDTA) and epinine as an internal standard. The supernatants wereinjected directly onto a Supelcosil C₁₈ (3 μM) column, connected to adetector (ESA Coulochem 5100A), set to 0,05/0,40 V.

Temperature Effects

A significant temperature decrease was obtained in rats followingsubcutaneous administration of 0.3 mg/kg or 1 mg/kg using oraladministration of the (R)-enantiomer of compound3-(N-isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman.

Method: In each test, thirty rats, weighing approx 250 g, housed in 6cages of 5 rats, are used. The rats have free access to food and water.Before the start of testing, they are numbered and left undisturbed forat last 1 hour. Before the administration of the compound, the bodytemperature of each rat is measured using a YSI 2100 tele-thermometer.The thermometer probe is inserted 10 cm into the rectum and left in pacefor thirty seconds.

The drug is then administered either subcutaneously or orally. In eachexperiment vehicle and 4 doses of drug are tested. One rat in each cagereceives each treatment. The order of treatment is rotated sincedisturbance to the cage increases the activity of the rats, and therebytheir body temperature. Thirty minutes after drug administration therats' body temperature are measured again. The procedure is repeated 60,90 and 120 minutes after drug administration. The resultant data on bodytemperature is subjected to analysis of variance. A significant group bytime interaction is taken as an indication of drug effect. To obtain theminimum effective dose, the mean temperature for each of the drugtreated groups are compared with that of the vehicle group at each timepoint using Dunnett's t-test with a level of significance of p<0.02. Anindication of bioavailability may be obtained by calculating the ratiobetween the minimum effective doses following oral and subcutaneousadministration.

WORKING EXAMPLES

The following examples will further illustrate the invention.

Example 1 3-Dipropylamino-5-trifluoromethanesulfonylchroman

3-Dipropylamino-5-hydroxychroman (Thorberg et al. Acta Pharm. Suec.24(1987), the contents of which are hereby incorporated herein byreference) (1.4 g, 4.0 mmol) and N,N-dimethylaminopyridine (0.1 g, 0.75mmol) were dissolved in 50 mL methylene dichloride (CH₂ Cl₂) and cooledto -30° C. 2,4,6-Collidine (0.75 mL, 5.7 mmol) was added followed bytrifluoromethane sulfonic anhydride (1.0 mL, 6.0 mmol).

The solution was stirred at -20° C. for 3 hours and then allowed toreach ambient temperature. The solution was washed with aqueous NaHCO₃,dried with Na₂ SO₄ and evaporated to dryness. The pale yellow oil wasfinally purified by flash chromatography (silica gel) by elution withethyl acetate/hexane 1:9.

Yield: 55%, Mp 125°-127° C. (oxalate).

Example 2 3-Dipropylamino-5-methyloxycarbonylchroman

3-Dipropylamino-5-trifluoromethanesulfonylchroman (Example 1; 4.43 g,11.6 mmol) was dissolved in 80 mL dimethylformamide/methanol 6:2 and thesolution was degassed (10 mmHg, 20° C., 15 min). PdOAc₂ (76 mg, 0.34mmol), 1,3-bis-diphenylphosphinopropane (141 mg, 0.34 mmol) andtriethylamine (3.5 mL, 25 mmol) were then added. The mixture was heatedto 70° C. under CO atmosphere and stirred for 5 hours. The solution wascooled, diluted with toluene (200 mL), washed with aqueous NaHCO₃, driedwith Na₂ SO₄ and evaporated to dryness. The oil was purified by flashchromatography (silica gel) by elution with ethyl acetate/hexane 1:8.

Yield: 76%, Mp 150°-152° C. (HCl-salt).

Example 3 3-Dipropylamino-5-carbamoylchroman

3-Dipropylamino-5-methyloxychroman (Example 2; 400 mg, 1.37 mmol) wasdissolved in 10 ml methanol and NaOH (60 mg, 1.5 mmol) in 2 mL H₂ O wasadded. The mixture was refluxed for 5 hours, cooled, filtered throughCelite and evaporated to dryness. The residue was refluxed in SOCl₂ (5mL, 68 mmol) for 30 minutes. The excess SOCl₂ was then removed in vacuoto give 3-dipropylamino-5-chloroformylchroman-HCL as a gum. The palebrown gum was dissolved in CH₂ Cl₂ (50 mL), and a stream of NH₃ (g) wasintroduced during 2 minutes. The solution was washed with aqueousNaHCO₃, dried with Na₂ SO₄ and evaporated to dryness. The oil waspurified by flash chromatography (silica gel) by elution with ethylacetate/hexane 1:4.

Yield 80%, ¹³ C-NMR: 172.0 154.9 136.5 126.9 120.4 119.1 118.6 67.8 53.052.6 26.1 22.4 21.9 14.1 11.7.

Example 4 3-dipropylamino-5-N,N-dimethylcarbamoylchroman

The title compound was prepared analogous to the procedure used inExample 3 starting from 3-dipropylamino-5-methyloxycarbonylchroman andsubstituting dimethylamine (g) in place of NH₃ (g). ¹³ C-NMR: 189.3170.3 149.9 137.4 126.7 126.1 124.9 65.8 64.7 48.2 47.7 30.7 26.0 15.110.9.

Example 5 3-Dipropylamino-5-N,N-diisopropylcarbamoylchroman

The title compound was prepared analogous to the procedure used inExample 3 starting from 3-dipropylamino-5-methyloxychroman. Mp 228°-230°C. (HCl-salt).

Example 6 3-Dipropylamino-5-N-methylcarbamoylchroman

The title compound was prepared analogous to the procedure used inExample 3 starting from 3-dipropylamino-5-methyloxycarbonylchroman andsubstituting methylamine (g) in place of NH₃ (g). Mp 95°-97° C.(oxalate).

Example 7 3-Dipropylamino-5-acetylchroman

3-Dipropylamino-5-chloroformylchroman*HCl (4.42 g, 13.4 mmol), preparedfrom 3-dipropylamino-5-methyloxycarbonylchroman (Example 2) analogous tothe procedure used in Example 3, in dry tetrahydrofuran (20 ml), wasadded to a pre-formed solution of lithium dimethylcuprate; prepared fromMeLi and CuI, in 200 mL tetrahydrofuran at -78° C. The solution wasstirred for 15 minutes at -78° C. and was then allowed to reach roomtemperature during 10 minutes. Then, 30 mL H₂ O was slowly added. Theorganic phase was decanted, dried with Na₂ SO₄ and evaporated todryness. The residue was purified by flash chromatography (silica gel)by elution with ethyl acetate/hexane 1:8. The title compound wascrystallized as salt from ethyl acetate. Mp 106°-108° C. (oxalate).

Example 8 3-Dipropylamino-5-cyclopropylcarbonylchroman

The title compound was prepared analogous to the procedure used inExample 7 substituting lithium dicyclopropylcuprate (J. Org. Chem., 41(22), 1976) in place of lithium dimethylcuprate. Mp 100°-102° C.(oxalate).

Example 9 3-Dipropylamino-5-tertbutylcarbonylchroman

The title compound was prepared analogous to the procedure used inExample 7 substituting lithium ditertbutylcuprate (from tertbutyllithiumand CuBr-Me₂ S) in place of lithium dimethylcuprate. Mp 118°-120° C.(oxalate).

Example 10 3-Dipropylamino-5-isopropylcarbonylchroman

The title compond was prepared analogous to the procedure used inExample 7 substituting magnesium diisopropylcuprate (fromisopropylmagnesium chloride and CuBr-Me₂ S) in place of lithiumdimethylcuprate. Mp 60°-62° C. (oxalate).

Example 11 3-Dipropylamino-5-(4-fluorophenylcarbonyl)chroman

The title compound was prepared analogous to the procedure in Example 7,substituting magnesiumdi(4-fluorophenyl)cuprate (from 4-fluorophenylmagnesium bromide and CuI) in place of lithium dimethylcuprate. Mp98.3°-98.4° C. (oxalate).

Example 12 3-Dipropylamino-5-(2-thienylcarbonyl)chroman

The title compound was prepared analogous to the procedure used inExample 7 substituting lithium di(2-thienyl)cuprate (from2-thienyllithiumand CuI) in place of lithium dimethylcuprate. Mp 87-88.5(oxalate).

Example 13 3-Dipropylamino-5-isopropenylchroman

Methyltriphenylphosphoniumbromide (0.62 g, 1.74 mmol) was dissolved indry ethyl ether (20 ml) under nitrogen at ambient temperature and n-BuLi(0.7 ml, 2.5M, 1.74 mmol) was added and the solution was stirred for 4hours.

3-Dipropylamino-5-acetylchroman (Example 7; 0.40 g, 1.45 mmol) wasdissolved in dry diethyl ether (2.0 ml) and this solution was added tothe previously formed Wittig-reagent.

The mixture was stirred at ambient temperature overnight. The solutionwas diluted with toluene and washed with water. Drying of the organicphase with Na₂ SO₄ and evaporation to dryness gave a solid, which wasfinally purified by flash chromatography by elution with ethylacetate/hexane 1:4. The collected fractions were evaporated and gave thetitle compound as a colourless oil. ¹³ C-NMR: 11.82 21.94 24.28 26.6952.79 53.64 67.70 115.03 115.13 118.73 120.07 126.83 144.88 145.27154.03.

Example 14 3-Dipropylamino-5-aminochroman

3-Dipropylamino-5-methyloxycarbonylchroman (Example 2; 1.0 g, 3.4 mmol)was dissolved in methanol (20 ml). Sodium hydroxide (0.16 g, 4.1 mmol)in water (1.0 ml) was added and the solution was refluxed with nitrogenovernight. The solution was evaporated to dryness, toluene (20 ml) wasadded and again the solution was evaporated to dryness. The residue wasdissolved in toluene 20 ml, diphenylphosphoryl azid (1.87 g, 6.8 mmol)was added and the solution was refluxed for 2 hours. Methanol (2.0 ml)was added and reflux was continued for 4 hours. The solution was cooled,washed with water and extracted with dilute HCl (aq.). The acidic waterphase was neutralized NaOH (aq.) and extracted with toluene. Thetoluene-phase was dried with sodium sulphate and evaporated to dryness.The residue was dissolved in ethanol containing 10% NaOH (20 ml) and thesolution was refluxed overnight. The solution was cooled and dilutedwith toluene. Washing with water, drying of the organic phase andevaporation to dryness afforded the title compound as an oil, which wasconverted to a dihydrochloride salt. Mp 173°-174° C.

Example 15 3-Dipropylamino-5-nitrochroman

3-Dipropylamino-5-aminochroman (Example 14; 0.050 g, 0.20 mmol) wasdissolved in a mixture of trifluoracetic acid (0.080 ml, 1.0 mmol) inwater (5 ml). The clear solution was cooled to 0°-4° C. Sodium nitrite(0.017 g, 2.5 mmol) in water (1.0 ml), was added dropwise with goodstirring. The solution was stirred for 15 minutes and neutralized withcalcium carbonate. A solution of sodium nitrite (0.50 g, 7.2 mmol) inwater (1.0 ml) was added followed by a mixture of copper sulfate (0.10g, 0.62 mmol) and copper (1) oxide in water (1.0 ml). The solution wasstirred at 0° C. for 20 minutes and then at ambient temperature for 2hours. The solution was extracted with diethyl ether. The organic phasewas dried with sodium sulfate and evaporated to dryness. The residue waspurified by flash chromatography on silica gel by elution with ethylacetate/hexane 1:9 to give the title compound. Mp 150°-151° C.(hydrochloride).

Example 16 3-Dipropylamino-5-azidochroman

3-Dipropylamino-5-aminochroman (Example 14; 0.050 g, 0.20 mmol) wasdiazotized according to the procedure of Example 15. After stirring for15 minutes, sodium azide (0.026 g, 0.4 mmol) in water (1.0 ml) wasadded. After stirring at 5° C. overninght the solution was worked-up andpurified according to the procedure of Example 15 to give the titlecompound. Mp 167°-168° C. (oxalate).

Example 17 3-Dipropylamino-5-(pyrrol-1-yl)chroman

3-Dipropylamino-5-aminochroman (Example 14; 0.60 g, 2.42 mmol) wasdissolved in acetic acid (10 ml) and 2,5-dimethoxytetrahydrofuran (0.40g, 3.0 mmol) was added. The solution was refluxed for 1 hour. Thesolution was neutralized with NaOH (aq.) and extracted with toluene. Theorganic phase was dried with sodium sulfate and evaporated to dryness.The residue was purified by flash chromatography on silica gel byelution with ethyl acetate/hexane 1:9 to give the title compound. ¹³C-NMR: 111.75 21.89 24.81 52.69 53.15 67.94 108.93 115.67 118.22 118.44121.87 127.22 141.47 155.27

Example 18 3-(Methyl(3-phenylpropyl)amino)-5-hydroxychroman

3-Amino-5-methoxychroman (Thorberg et al. Acta Pharm. Suec. 24(1987))(2.0 g, 9.28 mmol) was dissolved in methanol (50 ml) and pH was adjustedto 6.0 with acetic acid. The solution was cooled to 0° C. and sodiumcyanoborohydrid (0.87 g, 13.8 mmol) was added together with3-phenylpropanal (1.22 ml, 9.28 mmol), the cooling was withdrawn and thesolution was stirred at ambient temperature for 4 hours.Paraformaldehyde (0.42 g, 14 mmol) and sodium cyanoborohydride (0.87 g,9.28 mmol) was added and stirring was continued overnight at ambienttemperature. The solution was diluted with toluene and washed withwater. Drying with sodium sulfate and evaporation to dryness gives anoil. The oil was purified by flash chromatography on silica gel byelution with ethylacete/hexane 1:4. The collected fractions wereevaporated to give an oil. The oil was treated with HBr (47% aq.) at120° C. for 1 hour. The solution was cooled and neutralised with sodiumhydroxide and extracted with toluene. The organic phase was dried andevaporated to give the title compound as an oil. ¹³ C-NMR: 22.502 29.0933.47 38.19 53.66 67.75 102.04 109.20 110.46 125.78 127.05 128.36 142.20155.29 158.28.

Example 19 3-(methyl(3-phenylpropyl))amino-5-methyloxycarbonylchroman

3-(methyl(3-phenylpropyl))amino-5-hydroxychroman (Example 18; 1.0 g,3.37 mmol) was dissolved in CH₂ Cl₂ (20 ml) at -20° C. Pyridine (0.32ml,4 mmol), trifluoromethanesulfonic anhydride (0.65 ml, 5.9 mmol) anddimethylaminopyridine (DMAP), (0.041 g, 0.59 mmol) was added at -20° C.under nitrogen. The solution was stirred for 3 hours at -20° C. Coolingwas withdrawn and the solution was diluted with toluene, washed withsodium hydrogen carbonate (aq.), dried with sodium sulfate, filteredthrough silica gel and evaporated to dryness. The remaining oil wasdissolved in 13 ml degassed methanol/DMF 3:10. Palladium acetate (0.056g, 0.25 mmol), 1,3-bis(diphenylphosphino)-propane (0.103 g, 0.25 mmol)and triethyl amine (0.76 ml, 5 mmol) was added and the solution wasflushed with CO(g) under vigorous stirring. The pressure in the reactionvessel was raised to 20.2 KPa(e) with the aid of a CO(g)-cylinder fittedwith a regulator. Stirring was continued overnight at 75° C. Thepressure and temperature was normalized and the solution was dilutedwith toluene and washed with water.

The organic phase was dried and evaporated to dryness. The remaining oilwas purified by flash chromatography on silica gel by elution with ethylacetate/hexane 1:4. The collected fractions were evaporated to give thetitle compound as a colourless oil. ¹³ C-NMR: 26.88 29.00 33.20 37.8551.64 53.37 55.44 67.24 120.60 123.06 123.40 125.59 126.47 128.17 128.24130.36 142.01 154.93 167.29.

Example 20 3-(methyl(3-phenylpropyl))amino-5-N-methylcarbamoyl chroman

3-(methyl(3-phenylpropyl))amino-5-methyloxycarbonylchroman (Example 19;0.32 g, 0.94 mmol) was dissolved in methanol (10 ml). NaOH (0.08 g, 2mmol) in 1 ml water was added and the solution was refluxed overnightunder nitrogen. The solution was evaporated to dryness and co-evaporatedwith toluene (10 ml) to dryness again. The remaining solid was refluxedin SOCl₂ for 30 minutes and evaporated to dryness. The pale brown gumwas dissolved in tetrahydrofuran (THF) 20 ml and treated with methylamine (g) for 1 minute under vigorous stirring. The solution was dilutedwith toluene and washed with sodium hydrogen-carbonate (aq.). Drying andevaporation gave a gum, which was finally purified by flashchromatography on silica gel by elution with ethyl acetate/hexane 1:2.The collected fractions were evaporated to give the title compound as acolourless gum. Crystallization from ethyl acetate as oxalate gave whiteneedles. Mp 150°-151° C. (oxalate).

Example 21 3-Dipropylamino-5-trifluoromethanesulfonylthiochroman

3-Dipropylamino-5-hydroxybenzothiopyran (EP 0222 996; 420 mg, 1.58 mmol)and collidine (0.27 g, 0.29 mL) were dissolved in 15 mL of CH₂ Cl₂ andcooled to -30° C.

Trifluoromethanesulfonic anhydride (0.54 g, 0.32 mL) was added dropwiseand allowed to reach ambient temperature, and after 20 minutes dilutedwith methylendichloride.

The solution was washed with saturated NaHCO₃, dried with Na₂ SO₄, andevaporated in vacuo.

Chromatography on silica by elution with CHCl₃ gave 0.62 g of the titlecompound as the base. Yield: 98%. Mp. 37°-8° C.; ¹³ C NMR (200MHz--CDCl₃) PPM 148.3, 136.7, 128.4, 127.2, 126.3, 122.0, 117.1, 115.2,55.6, 52.5, 28.0, 26.6, 22.6, 11.8.

Example 22 3-Dipropylamino-5-methyloxycarbonylthiochroman

3-Dipropylamino-5-hydroxybenzothiopyran (EP 0222 996; 620 mg, 1.6 mmol)was dissolved in 11 mL of dimethylformamide/methanol (6:2) and thesolution was degassed (10 mm, 22° C., 15 min). Pd(OAc)₂ (11 mg),1,3-bis-diphenylphosphinopropane (19 mg), and triethylamine (0.48 mL,0.35 g) were added to the reaction mixture.

The mixture was heated to 70° C. under carbonmonoxide atmosphere andstirred for 5 hours. The solution was cooled, diluted with 30 mL oftoluene, washed with saturated NaHCO₃, dried with Na₂ SO₄, andevaporated in vacuo.

Chromatography on silica by elution using a gradient CHCl₃ →10%EtOAc/CHCl₃ gave 310 mg of the title compound (base) as a slightlyyellow oil; Yield: 64%. ¹³ C NMR (200 MHz--CDCl₃) PPM 168.2, 136.6,134.8, 131.6, 130.1, 126.5, 125.7, 56.7, 52.5, 52.1, 30.4, 28.0, 22.3,11.9.

Example 23 3-Dipropylamino-5-acetylthiochroman

3-Dipropylamino-5-methyloxycarbonylthiochroman (Example 22; 310 mg, 1.01mmol) was dissolved in 8 mL methanol and 60 mg of sodium hydroxide in 2mL water was added. After 5 hours reflux the mixture was cooled andevaporated in vacuo. The residue was dissolved in thionylchloride (5 ml)and refluxed for 1 hour. The excess thionylchloride was evaporated invacuo to obtain a gum.

The residual gum was dissolved in a minimal amount of tetrahydrofuranand added dropwise to a cooled (-78° C.) solution of lithium dimethylcuprate (2.02 mmol) in 20 mL of tetrahydrofuran.

The reaction mixture was stirred for 15 minutes at -78° C., then allowedto reach ambient temperature and after 10 minutes the reaction wasquenched with 0.9 mL of water.

The reaction was filtered through Celite and evaporated to dryness.

The residue were dissolved in ether, washed with saturated NaHCO₃,treated with brine, dried with Na₂ SO₄, and evaporated in vacuo toafford the crude base as an oil.

The crude residue was chromatographed on silica by elution using agradient of CHCl₃ →5% EtOAc/CHCl₃.

The hydrochloride salt was obtained by dissolving the pure base in etherand dropping an excess of an ethereal HCl solution. Recrystallization intrichloromethane/diethylether gave 92 mg of the title compound as awhite solid; Yield: 27%. Mp 141°-2° C.; ¹³ C NMR (200 MHz--CDCl₃) PPM201.9, 138.4, 135.9, 131.7, 131.2, 127.2, 127.0, 59.9, 54.1, 51.8, 29.9,27.9, 26.1, 18.6, 18.2, 11.6.

Example 24 5-Allyl-3-(dipropylamino)thiochroman

To a solution of 3-(dipropylamino)-5-trifluoromethanesulfonylthiochroman(Example 21; 1.28 g, 3.22 mmol),tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.064 mmol) and a fewcrystals of 2,6-di-t-butyl-4-methylphenol in 10 mL anhydrous toluene was1.17 g (1.1 mL, 3.53 mmol) tributylallyltin added neat. The resultingsolution was refluxed for 4 hours then pyridine (1 mL) was added to thecooled solution followed by 2.1 ml of a hydrogen fluoride-pyridinecomplex (Stille J. K. et al. JOC 52(1987) 422).

After stirring for 1 hour at room temperature, the reaction mixture wasdiluted with 50 ml diethyl ether and treated, successively, with 50 mL1M NaOH solution, H₂ O (×2), washed with a saturated NaCl solution anddried (NaSO₄). After filtering and removal of the solvent in vacuo, thecrude was obtained as a dark oil.

Chromatography on silica by elution using a gradient hexane →5%EtOAc/hexane gave 0.85 g of the title compound (base) as a slightlyyellow oil. Yield: 91%. ¹³ C NMR: (200 MHz--CDCl₃) PPM 139.0, 136.5,134.0, 133.0, 126.1, 125.9, 125.0, 116.0, 57.0, 52.6, 37.7, 29.5, 27.7,22.5, 11.9.

A portion of the base was taken out and made into the hydrochloride saltby dissolving the pure base in ether and dropping an excess of anethereal HCl solution. Recrystallizing (AcCN-Et20-hexane) gave a whitesolid. Mp 164°-5° C.

Example 25 3-(Dipropylamine)-5-propylthiochroman hydrochloride

To a stirred suspension of potassium azodicarboxylate (0.76 g, 3.9 mmol)(made fresh from diethyl azocarboxylate and potassium hydroxide) and5-allyl-3-(N,N-dipropylamino)thiochroman (Example 24; 0.4 g, 1.4 mmol)in 10 mL anhydrous methanol was added a solution of glacial aceticacid/methanol (1:4) until the yellow color (from the potassium salt)disappeared.

After 30 min stirring at room temperature more potassiumazodicarboxylate (200 mg) was added and again decomposed as before. Thisprocess was continued until analysis (GC) showed no starting materialremaining.

Upon completion, (2 hours and 4 additions of the potassium salt) thesolvent was removed in vacuo. To the remains, a 2M NaOH solution wasadded which was extracted (×2) with diethyl ether and the combinedorganic portions were treated with a saturated NaCl solution, and dried(Na₂ SO₄). The crude base was obtained as a light colored oil upon theremoval of the solvent in vacuo.

Chromatography on silica by elution using a gradient hexane--5%EtOAc/hexane gave the title compound (base) as a clear oil. Thehydrochloride salt was made by dissolvning the pure base in ether anddropping and an excess of an ethereal HCl solution. Recrystallizing(chloroform-Et₂ O) gave 0.30 g of a white solid. Yield: 66%. Mp150°-151° C. ¹³ C NMR: (on base, 200 MHz--CDCl₃) PPM 141.6 133.7 132.8,125.8, 125.6, 124.5, 57.1, 52.6, 35.3, 29.5, 27.6, 23.6, 22.4, 14.3,11.9.

Example 26 5-Methoxy-3-cyclopropylamino-chroman hydrochloride

The title compound was prepared according to known methods for reductiveamination (Clinton F. Lane Synthesis 1975 vol. 146 p 135) frommethoxy-3-chromanone and cyclopropylamine. Mp 188°-189° C.

Example 27 3-(N-Cyclopropylamino)-5-hydroxychroman

3-(N-Cyclopropylamino)-5-metoxychroman hydrochloride (5.6 g, 22 mmol)was suspended in CH₂ Cl₂ (140 mL) under N₂. The mixture was cooled on adry-ice/EtOH bath to -20° C. BBr₃ (4.1 mL, 44 mmol) dissolved in CH₂ Cl₂(60 mL) was added to the stirred mixture during 0.5 hour. The yellowclear solution was slowly warmed to 0° C. and kept at that temperatureuntil GC indicated a complete reaction (after 3-5 hours). Then thesolution was poured on crushed ice (200 g) and enough conc. NH₃ (aq.) tomake a pH of 8-9. The mixture was extracted with ether (3×200 mL). Thecollected ether phases were dried (MgSO₄), filtered and concentrated invacuo to afford a white solid. Crystallization from absolute EtOHafforded 3-(N-cyclopropylamino)-5-hydroxychroman (3.9 g, 88% yield) ascolourless needles. Mp 147°-148° C.

Example 28 3-(N-Cyclopropylamino)-5-trifluoromethane-sulfonyloxychroman

The title compound was prepared in analogy to the procedure used inexample 1 starting from the product formed in example 27. The base wascharacterized as the hydrochloride salt. Mp 207°-209° C. (decomp).

Example 29 3-(N-Cyclopropylamino)-5-(N-cyclopropyl)carbamoylchroman

3-(N-Cyclopropylamino)-5-trifluoromethane-sulfonyloxychroman (0.51 g,1,5 mmol) and triethylamine (0.46 mL, 3.3 mmol) was dissolved in DMF(7.5 mL) in a 200 mL hydrogenation bottle. The bottle was evacuated,followed by inlet of CO (repeated three times). Cyclopropylamine (2.9mL, 42 mmol), 1.3-bis(diphenylphosphino)propane (0.023 g, 55 μmol) andpalladium(II)acetat (0.12 g, 55 μmo) were added and then the mixture wasshaken at 70° C. for 3 hours at CO pressure of 2-2.5 bars. After coolingto room temperature the reaction mixture was partitioned with saturatedNaHCO₃ and ether (5×30 mL). The collected ether phases were dried(MgSO₄), filtered and concentrated in vacuo. Flash chromatography onsilica of the crude product with TH-F-EtOAc (8:92) as eluent afforded0.32 g of a white solid. Recrystallization from THF-ether gave3-(N-cyclo-propylamino)-5-(N-cyclopropyl)carbamoylchroman 0.17 g, 42%yield) as colourless needles. Mp 126°-127° C.

Example 30 3-Cyclopropylamino-5-[N-(2,6-xylidino)carbamoyl]-chromanhydrochloride

The sodium, salt of3-(N-cyclopropyl-N-trifluroacetyl)aminochroman-5-carboxylic acid (2.1mmol) obtained from example 28 after N-trifluoroacetylprotection,esterification (according to example 2) and subsequent hydrolyze andthionyl chloride (10 mL) under N₂ was refluxed for 2 hours. The excessof thionyl chloride was co-evaporated for severeal times with drytoluene on a rotatory evaporator. The acid chloride thus obtained wasdissolved in methylene chloride (10 mL) and added dropwise to a stirredsolution of 2,6-dimetylanilin (0.52 g, 4.3 mmol) and dry pyridine (6 mL)under N₂ at room temperature. When the reaction was complete (within 2hours according to TLC and capillary-GC) the volatiles were evaporatedon a rotary evaporator. The residue was redissolved in dry toulene andconcentrated in vacuo repeatedly (four times). Purification by flashchromatography on silica with THF-n-hexan (1:4) as eluent gave 0.72 g of3-(N-cyclopropyl-N-trifluoroacetylamino)-5-[N-(2.6-xylidino)carbamoyl]-chroman(72% yield) as a colourless solid. Mp 146°-149° C. (crystallized fromCHCl₃ -n-hexan). Part of this amide (0.44 g, 0.95 mmol) was added insmall portions during 15 minutes to a stirred suspension of lithiumtetrahydridoaluminate (0.072 g, 1.9 mmol) in 20 mL of dry THF (distilledfrom sodium bensophenone ketyl) under N₂. The mixture was stirred at 45°C. until TLC and capillary-GC indicated a complete reaction (afterfourty hours) and then quenched by careful addition of aqueous sodiumpotassium tartrate (0.5M).

After adjusting pH to 10 (concentrated ammonia) the solution wasextracted with ether (2×50 mL). The collected ether phases were dried(K₂ CO₃), filtered and concentrated in vacuo. The resulting oil waschromatographed on a silica column eluted with CHCl₃ -EtOAc(1:1) to give3-cyclopropylamino-5-[N-(2,6-xylidino)carbamoyl]-chroman (0.071 g; 22%overall yield) as an oil. A slight excess of HCl (approx. 3M in ether)was added dropwise to a stirred and chilled (+4° C.) solution of thebase from above and methanol (2-4 mL). The solvents were then rotaroryevaporated, ether was added and evaporated repeatedly to strip traces ofHCl. The oil solidified when the flask, filled with ether, was left inthe refrigerator overnight.

Crystallization from absolute EtOH afforded3-cyclopropylamino-5-[N-(2.6-xylidino)carbamoyl]chroman hydrochloride ascolourless needles. Mp 189°-191° C. (decomp).

Example 31 3-(N,n-Diallylamino)-5-methoxychroman and3-(N-Allylamino-5-methoxychroman

3-Amino-5-methoxychroman hydrochloride (Acta Pharm. Suec. 24 (1987) (5.0g, 23 mmol), allyl bromide (3.4 mL, 39 mmol), anhydrous K₂ CO₃ (9.6 g,69 mmol) and DMF (8.0 mL) were stirred under N₂ at room temperature for72 hours. Ether (150 mL) was added, the salts were filtered off bysuction and the clear filtrate was concentrated in vacuo. The residuewas purified on a silica column eluted with 1000 mL THF-n-hexan (1:9)and 1000 mL THF-hexan (1:3) to afford 3-(N-allylamino)-5-methoxychroman(1.7 g; 33% yield) and 3-(N,N-diallylamino)-5-methoxychroman (3.4 g, 56%yield) as oils. The diallylamino derivative above was isolated as thehydrochloride salt by addition of a slight excess of HCl (approx. 3M inether) to an ether solution of the amine. The crude HCl saltcrystallized on standing, with ether, in the cold. Mp 139°-140° C.

Example 32 3-(N-allyl-N-n-propylamino)-5-methoxychroman

3-(N-Allylamino)-5-methoxychroman (1.3 g, 5.9 mmol) prepared analogousto example 26, n-propyl iodide (2.1 mL, 21 mmol), anhyrous K₂ CO₃ (3.0g, 21 mmol) and acetonitrile (5.5 mL) were stirred under N₂ at 47° C.(oilbath temp) for five days until GC indicated complete reaction. Ether(40 mL) was added, the salts were filtered off by suction and the clearfiltrate was concentrated in vacuo to afford3-(N-allyl-N-n-propylamino)-5-methoxy chroman (1.24 g, 81% yield) as anoil. The base was precipitated from an ether solution by adding a slightexcess of HCl (approx. 3M in ether). Crystallization of the crude HClsalt afforded colourless needles. Mp 117°-118° C.

Example 33 3-(N-allyl-N-n-propylamino)-5-hydroxychroman

The title compound was prepared in analogy to the procedure used inexample 27 using the product obtained in example 32. Crystallizationfrom CHCl₃ -n-hexane gave colourless needles. Mp 78°-80° C.

Example 343-(N-Allyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychroman

The title compound was prepared in analogy to the procedure in example 1using the product from example 33 as starting material.

MS (EI, 70 eV) m/z 379 (M+, 8%), 350 (100%), 246 (10%).

Example 35 5-Acetyl-3-(N-Allyl-N-n-propylamino)chroman

3-(N-Allyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychroman (0.28g, 0.74 mmol), LiCl (0.097 g, 2.3 mmol), PdCl₂ (dppf) (0.031 g, 0.04mmol) and 2.6-di-t-butyl-4-methylphenol (0.005 g) were dissolved in DMF(5.0 mL) in a three-necked round-bottom flask (50 mL) with a magneticstirrer. The flask was evacuated, followed by inlet of CO (three times).Tetramethyltin (0.12 mL, 0.89 mmol) was added and then the mixture wasstirred under an atmosphere of CO (1 atm) at 120° C. (oilbath temp) for4 hours. The solvent was evaporated, the residue was partitioned betweenaqueous NH₃ (2M) and CH₂ Cl₂ (3×15 mL) and the organic phases were dried(Na₂ SO₄), filtered and concentrated in vacuo. Column chromatography onsilica with THF-n-hexane (1:9) as eluent afforded5-acetyl-3-(N-allyl-N-n-propylamino)chroman (0.078 g, 39% yield) as anoil. The base was precipitated from an ether solution by adding a slightexcess of HCl (approx. 3M in ether). The crude salt was collected anddried in vacuo at 40° C. to give a white amorphous powder. Mp 125°-127°C. PdCl₂ (dppf)=dichloro[1,1'-bis(diphenylphosphino)ferrocene]-palladium(II).

Example 36 3-isopropylamino-5-methoxychroman hydrochloride

The title compound was prepared analogous to the procedure used inexample 26 starting from 5-methoxy-3-chroman and isopropylamine. Mp 255°C.

Example 37 3-(N,N-isopropyl,n-propyl)amino-5-methoxychroman

A mixture of the product obtained in example 36 (14 g, 0,06 mol)1-iodopropane (15 g, 0,08 mol), K₂ CO₃ and acetonitile (250 ml) wasstirred with reflux for 4 days. After chromtography the desired productwas isolated as a colourless oil. GC-MS(CI-mode) M+1=264 (100%).

Example 38 3-(N,N-isopropyl,n-propyl)amino-5-hydroxychroman

The product from example 37 (10 g, 0,038 mol) was demethylated usingBBr₃ in dichloromethane. GC-MS(CI-mode) M+1=250 (100%).

Example 393-(N,N-isopropyl,n-propylamino)-5-trifluoromethanesulfonoxychroman

The title compound was prepared analogous to the procedure used inexample 1 using the product from example 38 as starting material.GC-MS(CI-mode) M+1=382 (100%).

Example 40 5-Acetyl-3-(N-isopropyl-N-n-propylamino)chroman hydrochloride

The title compound was prepared analogous to example 35 starting fromthe product obtained in example 39 and with the addition of CO in aParr-apparatus at 2 bar. Mp 170° C.

Example 41 3-(N-isopropyl-N-n-propylamino)-5-methyloxycarbonylchroman

The title compound was prepared analogous to the procedure used inexample 2 starting from the product obtained in example 39 (3 g, 0.016mol), Pd(OAC)₂ (75 mg), 1,3-bis(diphenylphosphine) propane (150 mg), DMF(50 ml) and methanol (25 ml) in a Parr-apparatus under CO pressure (2bar) at 70° C. for 6 hours. GC-MS(CI-mode) M+1=292 (100%).

Example 42 3-(N-isopropyl-N-n-propylamino)-5-(N-methyl)-carbamoylchromanhydrochloride

The product obtained from example 41 (1 g, 0.0034 mol), NaCN (50 mg),methanol (30 ml) and a saturated water solution of CH₃ NH₂ (5 ml) wasreacted in a steel wessel at 80° C. over night. After work up thecolourless oil was transferred to the hydrochloride salt. Mp 123° C.

Example 43 3-(N-isopropyl-N-n-propylamino)-5-(N-ethyl)-carbamoylchromanhydrochloride

The title compound was prepared analogous to the procedure used inexample 42, starting from the product obtained in example 41 (1 g,0.0034 mol), KCN (50 mg), methanol (40 ml) and ethylamine (5 ml, 70%water solution) in a steel wessel at 80° C. for 4 days. Chromotographicwork up gave a colourless oil which was converted to the HCL-salt. Mp198° C.

Example 443-N-Cyclopropylmethyl-N-n-propylamino)-5-(N-cyclopropylmethyl)carbamoylchroman

The title compound was prepared from3-(N-cyclopropylmethyl-N-n-propylamino)-5-trifluoromethanesulfoxyloxychroman(1.08 g, 0,0026 mol) obtain analogous to the example 36-39, 1,3-bis(diphenyl phosphine)propane (40 g), palladium (II) acetate (22 mg), andcyclopropylmethylamine (2.3, 0.0264 mol) in 30 ml DMF was placed in aParr glass essel. CO at 2 bar was added and the mixture was shaken at60° C. for 4 hours. After work up and chromatographic purifications thedesired compound was obtained as white crystalls with mp 124° C. (base)as needles. Mp 94°-95° C.

Example 45 3-(N-cyclopropyl-N-n-propylamino)-5-phenylchromanhydrochloride

The title compound was prepared from a mixture of3-(N-cyclopropyl-N-n-propylamino)-5-trifluoromethylsulfonyloxychromanobtained analogous to the example 36-39 (2 g, 5.1 mmol),trimethylphenylstannane (1.8 g, 4.8 mmol), tetratis(triphenylphosphine)-palladium (0) (280 mg, 0.24 mmol).

Lithiumchloride (600 mg, 14.4 mmol) and 2.6-di-t-butyl-4-methylphenol in60 ml dioxane and 6 ml DMF was stirred at 105° C. In a steel wessel for3 days. The mixture was filtered and extracted. Chromatographicpurification on an alumenia column gave the desired compound in 55%yield. The compound was isolated as the hydrochloride salt. Mp 160° C.

Example 46 3-(N,N-dipropylamino)-5-N-cyclopropyl)-carbamoylthiochroman

3-(N,N-Dipropylamino)-5-trifluoromethanesulfonyloxythiochroman (0.70 g,1.76 mmol), triethylamine (0.39 g, 0.54 mL, 3.9 mmol) and DMF (5 mL)were mixed together and the solution was degassed (10 mmHg, RT, 15 min)then subjected to CO atmosphere (×3). Then palladium (II) acetate (12mg), 1,3-bis-diphenylphospinopropane (22 mg), and cyclopropylamine (3.0g, 3.7 mL, 52.8 mmol) were added. The resulting mixture was againsubjected to CO atmosphere and heated to 70° C. with stirring for 4hours. The solution was cooled, evaporated in vacuo (vacuum pump), thendiluted with ethyl acetate. The mixture was washed with bicarbonatesolution (three times), treated with brine, dried (Na₂ SO₄), andevaporated in vacuo to give crude. Chromatography on silica (eluent: 50%EtOAc/hexane) gave 0.38 g as white hard crystals (64% yield).

Mp 109°-110° C. ¹³ C NMR: (200 MHz--CDCl₃) PPM 171.1 137.8 134.5 133.2128.0 126.0 122.7 56.5 52.5 29.9 28.1 23.0 22.4 11.9 7.0.

Example 47 3-(N.N-Dipropylamino)-5-methyloxycarbonylthiochroman

(3-(N,N-Dipropylamino)-5-trifluoromethanesulfonylthiochroman (620 mg,1.6 mmol) was dissolved in 11 mL of DMF/methanol 6:2 and the solutionwas degassed for 15 min. Pd(OAc)₂ (11 mg),1,3-bis-diphenyl-phosphinopropane (19 mg), and triethylamine (0.48 mL,0.35 g) were added to the reaction mixture. The mixture was heated to70° C. under carbonmonoxide atmosphere and stirred for 5 hours. Thesolution was cooled, diluted with 30 mL of toluene, washed withsaturated NaHCO₃, dried (Na₂ SO₄) and evaporated in vacuo.

Chromatography on silica (eluent: gradient CHCl₃ →10% EtOAC/CHCl₃) gave310 mg (64% yield) of the title compound (base) as a slightly yellowoil. ¹³ C NMR: (200 MHz--CDCl₃) PPM 168.2, 136.6, 134.8, 131.6, 130.1,126.5, 125.7, 56.7, 52.5, 52.1, 30.4, 28.0, 22.3, 11.9.

Example 48 3-(N-Isopropyl-N-n-propylamino)-5-phenyl-1-oxothiochroman

3-(N-Isopropyl-N-n-propylamino)-5-phenylthiochroman hydrochloride (310mg, 0.86 mmol) was dissolved in 6 mL chloroform and to the cooledsolution (ice-bath) was m-chloroperbenzoic acid (348 mg, 1.72 mmol)added in one portion.

The reaction was allowed to stir at room temperature for 18 h. Thesolvent was removed in vacuo and the remains were extracted withether/2M NaOH, treated with brine and dried (Na). The solvent wasevaporated in vacuo to give the crude mixture.

Chromatography on silica (eluent: 25% EtOAc/CH₂ Cl₂) gave 79 mg (27%yield) of the desired sulphoxide as a diastereomeric mixture (18:82 byGC) obtained as an off-white solid. Mp 109°-112° C.

Example 495-(2-Furanyl)-3-(N-isopropyl-N-n-propylamino)-1-oxothiochroman

5-(2-Furanyl)-3-(N-isopropyl-N-n-propylamino)thiochroman hydrochloride(341 mg, 0.97 mmol) was dissolved in 7 mL methylene chloride and cooledto -20° C. m-Chloroperbenzoic acid (258 mg, 1,27 mmol) was added in oneportion and the reaction was allowed to stir at room temperature for 18h.

The solvent was removed in vacuo and the remains were extracted withether/2M NaOH, treated with brine and dried (Na₂ SO₄). The solvent wasevaporated in vacuo to give the crude mixture.

Chromatography on silica (eluent: 25% EtOAc/CH₂ Cl₂) gave 35 mg of thenon-polar diastereomer of the title compound, 75 mg of the polar (major)diastereomer of the title compound and 92 mg as a diastereomeric mixture(25:75 by GC) to give a combined yield of 63%.

Non-polar (minor) isomer (off-white solid): Mp 63°-65° C. Polar (major)isomer (off-white solid): Mp 83°-85° C.

Example 505-(2-Furanyl)-3-(N-isopropyl-N-n-propylamino)-1,1-di-oxothiochroman

5-(2-Furanyl)-3-(N-isopropyl-N-n-propylamino)-1-oxothiochroman (as adiastereomeric mixture (25:75 by GC)) (92 mg, 0.29 mmol) was dissolvedin ether and HCl in ether was added dropwise until the solution wasacidic. The solvent was removed in vacuo. The white solid obtained wasdissolved in 3 mL methylene chloride and the solution was cooled to -15°C.

m-Chloroperbenzoic acid (118 mg, 0.58 mmol) was added in one portion andthe reaction was allowed to stir at room temperature for 18 h. Only theminor diastereomer reacted to give the desired sulphone due to stericreasons. The solvent was removed in vacuo and the remains were extractedwith ether/2M NaOH, treated with brine and dried (Na₂ SO₄).

The solvent was evaporated in vacuo to give the crude mixture.

Chromatography on preparative TLC(eluent: 20% EtOAc/CH₂ Cl₂) gave 5 mg(5% yield) of the title compound.

MS 347 ¹³ C NMR (200 MHz--CDCl₃) PPM 151.7, 143.0, 139.3, 132.3, 131.6,127.5, 125.6, 123.5, 111.7, 110.5, 54.3, 51.3, 49.4, 47.4, 34.4, 23.3,21.7, 20.0, 11.8.

Example 515-(2-Furanyl)-3-(N-isopropyl-N-n-propylamino)thiochromanhydrochloride

To a solution of3-(N-isopropyl-N-n-propylamino)-5-trifluoromethanesulfonylthiochroman(0.92 g, 2.31 mmol), ethanol (10.2 mL), lithium chloride (0.20 g, 4.8mmol), 2M sodium carbonate (3.4 mL), andtetrakis(triphenylphosphine)palladium(O) (49 mg, 0.042 mmol) dissolvedin toluene (23 mL) was 2-furanylboronic acid (0.62 g, 4.6 mmol) added inone portion under nitrogen. The resulting solution was heated to 95° C.for 2 hours then the reaction was allowed to cool. The reaction wasfiltered and the solvent was evaporated in vacuo. The remains were takeninto ether, washed with 2M NH₃, treated with brine and dried (NaSO₄).Removal of the solvent in vacuo gave the crude compound.

Chromatography on silica (eluent: 3% EtOAc/CHCl₃) gave 0.68 g (93%yield) of the title compound (base) as a slightly yellow oil.

The hydrochloride salt was made by dissolving the pure base in ether anddropping an excess of an ethereal HCl then recrystallized (EtOAc/ether)to give colorless crystals. Mp 145°-147° C.

Example 52 5-Isopropylamido-3-(N-isopropyl-N-n-propylamine)thiochroman

3-(N-Isopropyl-N-n-propylamino)-5-trifluoromethnaesulfonylthiochroman(0.99 g, 2.49 mmol) was dissolved in dioxane (15 mL) and the solutionwas degassed (10 mmHg, RT) then subjected to CO atmosphere (×3).

Isopropylamine (1.1 mL, 12.5 mmol), palladium acetate (15 mg) and1,3-bis-di-phenylphospinopropane (29 mg) were added. The resultingmixture was again subjected to CO atmosphere and heated to 80° C. withstirring for 4 h.

The solution was cooled, evaporated in vacuo (vacuum pump), then dilutedwith ether. The mixture was washed with a 2M NH₃ solution (×2), treatedwith brine, dried (NaSO₄) and evaporated in vacuo to give crude.

Chromatography on silica (eluent: 30% EtOAc/hexane) gave 0.76 g oil (87%yield) that crystallized and was recrystallized (hexane) to give a whitesolid. Mp 90°-91° C.

Example 533-(N-Isopropyl-N-n-propylamino)-5-trifluoromethanesulfonylthiochroman

5-Hydroxy-3-(N-isopropyl-N-n-propylamino)thiochroman (3.13 g, 11.9 mmol)and collidine (2.02 g, 2.2 mL, 16.7 mmol) were dissolved in 100 mL ofCH₂ Cl₂ and cooled to -30° C. Trifluoromethanesulfonic anhydride (4.03g, 2.4 mL, 14.3 mmol) was added dropwise and allowed to warm to ambienttemperature, and after 20 min diluted with CH₂ Cl₂. The solution waswashed with saturated NaHCO₃, dried (Na₂ SO₄) and evaporated in vacuo.

Chromatography on silica (eluent: 3% EtOAc/hexane) gave 3.9 g (83%yield) of the title compound as a slightly yellow oil. MS 397. ¹³ C NMR:(200 MHz--CDCl₃) PPM 148.3, 136.7, 128.8, 127.2, 126.3, 121.9, 117.0,115.5, 52.8, 48.8, 47.1, 30.2, 28.8, 23.7, 21.2, 20.9, 11.7.

Example 543-(N-Isopropyl-N-n-propylamino)-5-methyloxycarbonylthiochroman

3-(N-Isopropyl-N-n-propylamino)-5-trifluoromethanesulfonylthiochroman(0.97 g, 2.44 mmol) was dissolved in 17 mL of DMF/methanol 6:2 and thesolution was degassed for 15 min. Pd(OAc)₂ (17 mg),1,3-bis-diphenyl-phosphinopropane (29 mg) and triethylamine (0.54 g,0.75 mL, 5.4 mmol) were added to the reaction mixture. The mixture washeated to 70° C. under carbonmonoxide atmosphere and stirred for 4hours.

The solution was cooled, diluted with toluene, washed with saturatedNaHCO₃, dried (Na₂ SO₄) and evaporated in vacuo.

Chromatography on silica (eluent: 5% EtOAc/hexane) gave 0.69 g (92%yield) of the title compound (base) as a clear oil.

MS 307. ¹³ C NMR: (200 MHz--CDCl₃) PPM 168.3, 137.0, 134.8, 131.6,130.1, 126.5, 125.7, 53.9, 52.2, 48.9, 47.3, 32.7, 30.1, 23.8, 21.1,11.8.

Example 553-(N-isopropyl-N-n-propylamino)-5-phenylthiochromanhydrochloride.

To a solution of3-(N-isopropyl-N-n-propylamino)-5-trifluoromethanesulfonylthiochroman(0.95 g, 2.39 mmol), ethanol (10.5 mL), lithium chloride (0.20 g, 4.8mmol), 2M sodium carbonate (3.5 mL), andtetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) dissolvedin toluene (23 mL) was phenylboronic acid (0.35 g, 2.9 mmol) added inone portion under nitrogen. The resulting solution was heated to 95° C.for 5 hours then the reaction was allowed to cool. The reaction wasfiltered and the solvent was evaporated in vacuo. The remains were takeninto ether, washed with 2M NH₃, treated with brine and dried (NaSO₄).Removal of the solvent in vacuo gave the crude compound.

Chromatography on silica (eluent: CH₂ Cl₂) gave 0.73 g (94% yield) ofthe title compound (base) as an oil.

The hydrochloride salt was made by dissolving the pure base in ether anddropping an axcess of an ethereal HCl then recrystallized (EtOAc/ether)to give a slightly yellow solid. Mp 110°-112° C.

Example 56 (R)-3-(N-Isopropyl,N-n-propylamino)5-(3-thiophene)chroman.

(R)-3-(N-isopropyl,N-n-propylamino)5-trifluoromethanesulfonyloxychroman(0.3 g, 0,8 mmol), 3-thiopheneboronic acid (0.2 g, 1.6 mmol), LiCl (0.07g, 1.6 mmol), NA₂ CO₃ (2M, 3 mL), EtOH (7 mL) and toluene (15 mL) wasmixed in a three-necked round-bottom flask under a nitrogen atmosphere.The catalyst (Pd(PPh₃)₄, was added and the reaction mixture was stirredat 90° C. for 4 h. The solvent was removed in vacuo until about 15 mLwas left before diluted with diethyl ether, washed (NH₃, 2M) and dried(Mg SO₄). The solvent was removed in vacuo to give a brownish oilyresidue which was purified by flash-chromatography (SiO₂, CH₃ Cl_(2/)EtOAc, 10:1) to give the title compound in 80% yield (0.2g).α(base)=-40°

(MeOH, 0.1M, 22° C.). The HCl-salt was precipitated from diethyl etherat 0° C. Mp. 174°-175° C.

Example 57 (R)-3-(N-Isopropyl,N-n-propylamino)5-(2-thiophene)chroman.

(R)-3-(N-Isopropyl,N-n-propylamino)-5-trifluoromethanesulfonyloxychroman(0.4 g, 1.1 mmol), 2-thiophene-boronic acid (0.27g, 2.1 mmol), LiCl(0.09 g, 2.1 mmol), Na₂ CO₃ (2M, 3 mL), EtOH (7 mL) and toluene wasmixed under a nitrogen atmosphere before Pd(PPh₃)₄ (0.03 g, catalyticamount) was added. The mixture was then stirred for 8 hours at 90° C.

The solvent was removed in vacuo until 10 mL was left. The residue wasdiluted with diethyl ether, washed with NH3 (2M) and dried (MgSO₄). Thesolvent was removed in vacuo to give a brownish oily residue which waspurified by flash-chromatography (SiO₂, CH₂ Cl₂ /EtOAc, 10:1) to givethe title compound in 94% in yield (0.3 g). α(base)=-36° (MeOH, 0.1M,22° C.). The HCl-salt was precipitated from diethyl ether at 0° C. Mp189°-191° C.

Example 58(R)-5-Isopropoxycarbonyl,3-(N-isopropyl,N-n-propylamino)chroman

(R)-3-(N-Isopropyl,N-n-propylamino)5-trifluoromethanesulfonyloxychroman(0.4 g, 1.1 mmol), triethylamine (0.2 g, 2.2 mmol), DMF (6 mL) andisopropanol (2 mL) was mixed in a three-necked 50 mL round-bottom flask.The flask was evacuated followed by inlet of CO-gas (repeated threetimes, CO in water-byrett) before 1,3-bis(diphenylphosfino)propane (0.02g, catalytic amount) and palladium(II)acetate (0.08 g, catalytic amount)was added.

The mixture was stirred at 80° C. for 7 h. The sovent was removed invacuo and the residue was dissolved in diethyl ether, washed with NH₃(2M) and dried (MgSO₄). The solvent was removed in vacuo to give ayellowish oily residue which was purified by flash chromatography (SiO₂,SC₂ Cl₂ /EtOAc, 10:1) to give the title compound in 66% yield (0.2 g).α(base)=-110.5° (MeOH, 0.1M, 22° C). the HCl-salt was precipitated fromdiethyl ether at 0° C. and recrystallized from EtOAc/diethyl ether. Mp153°-155° C.

Example 59(R)-3-(N-isopropyl,N-n-propylamino)5-(2-N-thiazoleaminocarbonyl)chroman

(R)-5-Chlorocarbonyl,3-(N-isopropyl,N-n-propylamino)chroman (0.65 g, 2.3mmol) and 2-aminothiazole (0.68, 6.8 mmol), dissolved in methylenechloride (50 mL), was stirred at room temperature for 2 h. The reactionmixture was washed with 1M NH₃ and dried (Na₂ SO₄). Removal of solventin vacuo gave a brownish oily residue which was purified by flashchromotagraphy (SiO₂, CH₂ Cl₂ /EtOAc, 10:1) to give the title compoundin 43% yield (0.35 g). The HCl-salt was precipitated from diethyl etherat 0° C. and then recrystallized from EtOAc/diethyl ether.α(HCl-salt)=-20.0° C.). Sinters<140° C.

Example 60 (R)-3-(N-Isopropyl,N-n-propylamino)5-(3-pyridine)chroman

(R)-3(N-isopropyl,N-n-propylamino)5-trifluoromethanesulfonyloxychroman(0.37 g, 0.96 mmol) was dissolved in toluene under a nitrogenatmosphere. Ethanol (7 mL), 2M Na₂ CO₃ (3 mL), LiCl (0.08 g, 1.9 mmol)3-pyridineboronic acid (0.7, 0.5 mmol) and finally Pd(PPh₃)₄ (0.04 g)was added and the reaction mixture was refluxed for 6 h. The solventremoved in vacuo until 10 mL was left. The residue was diluted withdiethyl ether, washed with 2M NH₃ and dried (MgSO₄). Removal of thesolvent gave yellowish oily residue which was purified by flashchromatography (SiO₂, CH₂ Cl₂ /EtOAc, 5:1) to give the title compound in94% yield (0.28 g) α(base)=-47.6° (MeOH, 0.1M, 21° C.). The dioxalatewas precipitated by addition of oxalic acid (2.2 eq), dissoved indiethyl ether, to a solution of the base in diethyl ether. Then salt wasthe recrystallized from EtOH/diethyl ether. Sinters <135° C.

Example 61 (R)-3-(N-Isopropyl,N-n-propylamino)-5-phenylchroman

(R)-3-(N-Isopropyl,N-n-propylamino)-5-trifluoromethanesulfonyloxychroman(1 g, 2.6 mmol) was dissolved in toluene (25 mL) under a nitrogenatmosphere. Ethanol (11.5 mL), LiCl (0.22 g, 5.2 mmol), Na₂ CO₃ (2M, 3.8mL), Pd(PPh₃)₄ (0.054 g, 0.047 mmol) and phenylboronic acid (0.38 g, 3.1mmol) were added and the reaction mixture was stirred at 90° C. for 7 h.The solvent removed in vacuo until 15 mL was left. The residue wasdiluted with diethyl ether, washed with NH₃ (2M) twice and dried(MgSO₄). Removal of the solvent in vacuo gave a yellow-brownish oilyresidue which was purified by flash chromatography )SiO₂, CH₂ Cl₂) togive the title compound in 86% yield (0.7 g). α=-50.7° (MeOH, 0.1M, 22°C.). The HCl-salt was precipitated from ether by the slow addition ofHCl in ether to an ice-cold solution of the base. The crude salt wasrecrystallized from EtOAc/diethyl ether to give 650 mg of needle-likecrystals. Mp. 141°-142° C.

Example 62 (R)-3-(N-isopropyl,N-n-propylamino)5-carbamoylchroman

A solution of (R)-5-chlorocabonyl,3-(N-isopropyl,N-n-propylamino)chroman(0.37 g, 1.3 mmol) in methylene chloride (30 mL) was carefully flushedwith NH₃ for 30s. A white precipitate was immediately formed. Thereaction mixture was then stirred for 30 min at room temperature beforeit was washed with water and dried (MgSO₄). The solvent was removed invacuo to give a crude oil which was purified by flash chromatography(SiO₂, CH₂ Cl₂ /EtOAc; 10:1). The title compound was obtained in 58%yield (0.21 g ) as colourless crystals from diethyl ether/hexane.

α=-115.8°, MeHO, 0.1M, 21° C.). Mp. 120.6°-122° C. This compound is avery strong agonist.

Example 63(R)-3-(N-isopropyl,N-n-propylamino)5-N-phenylaminocarbonylchroman

(R)-5-chloracarbonyl,3-(N-isopropyl,N-n-propylamino)chroman (0.65 g, 2.3mmol) and aniline (0.86 g, 9.2 mmol), dissolved in methylene chloride(30 mL), was stirred at room temperature for 1 h. The reaction mixturewas then washed with 2M NH₃ and dried (Na₂ SO₄). The solvent was removedin vacuo to give a brownish oily residue which was purified by flashchromatography (SiO₂, CH₂ Cl₂ /EtOAc, 5:1) to give the pure titlecompound in 91% yield (0.75 g). α(base=-91.3° (MeOH, 0.1M, 21° C.). TheHCl-salt was precipitated from ether at 0° C. and then recrystallizedfrom EtOAc/diethyl ether. Sinters <120° C.

Example 64 (R)-5-(2-Furyl)3-N-isopropyl,N-n-propylaminochroman

(R)-3-(N-Isopropyl,N-n-propylamino)5-trifluoromethanesulfonyloxychroman(0.4 g, 1 mmol), 2-furylboronic acid (0.3 g, 2.6 mmol), LiCl (0.09 g, 2mmol), NaCo₃ (2M, 3 mL), ethanol (7 mL) and toluene (15 mL) was mixed,under nitrogen, in a three necked 100 mL round bottom flask equippedwith a condenser. Finally was Pd(PPh3) (0.03 g, catalytic amount) addedand the reaction mixture was refluxed for 2 hours before it was dilutedwith diethyl ether, washed (2M NH₃) and dried (Na₂ SO₄). The solvent wasremoved in vacuo to give a brownish oily residue which was purified byflash chromatography (SiO₂, CH₂ Cl₂ /EtOAc, 10:1) to give the pure titlecompound in 95% yield (0.3 g). α(base)=-57.4° (MeOH 0.1M, 21° C.). TheHCl-salt was precipitated from diethyl ether at 0° C. and thenrecrystallized from EtOAc/diethyl ether. mp=151°-152° C.

Example 65 5-Formyl-3-(N-isopropyl-N-propylamino)chroman

a) 5-Hydroxymethyl-3-(N-isopropyl-N-propylamino)chroman

5-Methyloxycarbonyl-3-(N-isopropyl-N-propylamino)chroman (0.69 g, 2.36mmol) was dissolved in 25 mL of dry methylene chloride and cooled to-78° C. A 1M solution of diisobutylaluminum hydride in hexane (6.6 mL)was added dropwise and the reaction was allowed to warm to roomtemperature for 50 min. A 1M solution of KOH was added dropwise and thenthe reaction was put into the refrigerator over night. The solution waspoured through a pad of Na₂ SO₄, dried (Na₂ SO₄), filtered and thesolvent removed in vacuo to give 0.60 g (97% yield) of the titlecompound as a clear oil.

¹³ C NMR: (200 MHz--CDCl₃) PPM 154.6 140.1, 127.0, 120.5, 119.8, 116.3,69.0, 62.9, 50.9, 48.9, 47.8, 27.2, 24.3, 21.0, 20.1, 11.7

b) 5-Formyl-3-(N-isopropyl-N-propylamino)chroman

5-Hydroxymethyl-3-(N-isopropyl-N-propylamino)chroman (0.60 g, 2.27 mmol)was dissolved in 50 mL methylene chloride and to the solution manganesedioxide (1.98 g, 22.7 mmol) was added in one portion and the reactionwas allowed to stir at room temperature for 8 days.

The reaction was filtered through a pad of celite, washed with warmmethylene chloride and the solvent was removed in vacuo.

Chromatography on silica (eluent: 5% EtOAc/hexane) gave 0.33 g (56%yield) of the title compound (base) as a slightly yellow oil.

¹³ C NMR: (200 MHz--CDCl₃) PPM 193.0, 155.1, 135.0, 127.0, 126.8, 124.0,122.4, 69.2, 50.3, 48.9, 47.7, 28.1, 24.3, 21.1, 19.9, 11.6.

Example 66 (R)-3-(N-isobutyl)amino-5-(N-methyl)-carbamoylchroman

To a stirred solution of (R)-3-amino-5-(N-methyl)-carbamoylchroman inmethanol (25 mL) isobutyraldehyde (0.33 g, 4.60 mmol) was added. Themixture was cooled to 0° C. and sodium cyanoborohydride (0.34 g, 5.44mmol) was added in protions. pH was adjusted to approximately pH 5 withacetic acid. The mixture was stirred at room temperature for 3.5 hours.A small amount of isobutyraldehyde (15 mg, 0.21 mmol) was added due toincomplete reaction and the mixture was stirred for another 20 min. Thesolvent was evaporated and the residue was partitioned between ether(100 mL) and 1M NH₃ -solution (20 mL). The layers were separated and theaquous phase was extracted with ether (3×50 mL). The combined organiclayers were washed with 1M NH₃ -solution (20 mL), dried (MgSO₄),filtered and evaporated. The residue was chromatographed on a shortcolumn of silica gel (eluent: EtOAc+0.5% conc. NH₃). Pure fractions werepooled and evaporated to give 0.81 g (74%) of the title compound as awhite solid: mp 111°-112.8° C. [α]²¹ : -33.1 (c=2.6, MeOH).

Example 67(R)-3-(N-isobutyl-N-propyl)amino-5-(N-methyl)-carbamoylchromanhydrochloride

Propionaldehyde (0.11 g; 131 μL, 1.82 mmol) was added to a stirred, icecooled solution of (R)-3-(N-isobutyl)amino-5-(N-methyl)-carbamoylchroman(0.43 g, 1.65 mmol) in methanol(10 mL). Sodium cyanoborohydride (0.14 g,2.15 mmol) was added in portions and pH was adjusted to pH 5 with aceticacid. The reaction mixture was stirred at room temperature. In order tocomplete the reaction several additions of propionaldehyde had to bedone. Totally 0.20 g; 248 μL, 3.44 mmol was added to the reactionmixture.

The solvent was removed in vacuo and the residue was partitioned betweenether (100 mL) and 1M NH₃ -solution (20 mL). The layers were separatedand the aquous layer was extracted with ether (50 mL). The combinedorganic layers were washed with brine (20 mL), dried (MgSO₄), filteredand evaporated. The crude product was filtered through a short column ofsilica gel (eluent: EtOAc: hexane 1:1+0.5% conc. NH₃). The eluent wasremoved in vacuo giving an uncoloured oil which was converted into thehydrochloride in HCl/ether:

Example 68(R)-3-[N-(2-pyridyl)methyl]amino-5-(N-methyl)-carbamoylchroman

(R)-3-amino-5-(N-methyl)-carbamoylchroman (1.02 g, 4.96 mmol) wasdissolved in methanol (30 mL). The reaction vessel was coated withaluminium foil to prevent exponation to light. The solution was cooledto 0° C. and picolinaldehyde (0.69 g; 617 μL; 6.45 mmol) was added.Sodium cyanoborohydride (0.53 g, 8.44 g) was then added in portions andpH was adjusted to pH 5.5 with acetic acid.

The reaction mixture was stirred at room temperature for 2 hours.Another 50 μL, 0.52 mmol of picolinaldehyde was added in order tocomplete the reaction and the mixture was stirred for 1 hour. Thesolvent was removed in vacuo and the residue was partitioned betweenether (100 mL) and 1M NH₃ -solution (25 mL). The layers were separatedand the aquous layer was extracted with ether (2×50 mL). The combinedether extracts did not contain any reasonable amount of the desiredproduct. Therefore, the aquous phase, with an addition of NaCl (s), wasextracted with EtOAc (4×100 mL). The combined organic layers were dried(Na₂ SO₄), filtered and evaporated to give a yellow solid.Recrystallisation from EtOAc: hexane (35:65) gave a white solid whichhad to be further purified by column chromatography (EtOAc:EtOH 1:1+1%conc. NH₃) yielding 0.64 g (43%) of the title compound as a white solid:mp 141.2°-141.6° C.; [α]²¹ =-26.2 (c=3.0, MeOH).

Example 69 (R)-3-(N-hexyl)amino-5-phenylchroman hydrochloride

To a solution of (R)-3-amino-5-phenylchroman (1.00 g, 4.44 mmol) inmethanol (25 mL), hexanal (0.49 g; 0.60 mL, 4.91 mmol) was added whilestirring. The mixture was cooled to 0° C. and sodium cyanoborohydride(0.36 g, 5.78 mmol) was added in portions. pH was adjusted to pH 5.5with acetic acid. The reaction mixture was stirred at room temperaturefor 2.5 hours. Due to incomplete conversion of the starting materialanother 300 μL (2.46 mmol) of hexanal was added in portions. The solventwas removed under reduced pressure and the residue was partitionedbetween ether (100 mL) and 1M NH₃ -solution (25 mL). The layers wereseparated and the ether extract was washed with 1M NH₃ -solution (25mL). The aquous phase was removed and the ether phase was shaken with 1MHCl-solution (10 mL). The hydrochloride salt crystallized directly inthe separatory funnel and was filtered off and washed with ice cooledhexane. After drying there was obtained 0.86 g (56%) of the titlecompound as white crystals: mp 171.6°-174.2° C.; [α]²¹ =+82.8(c=1,MeOH).

Example 70 (R)-3-(N-methyl-N-propyl)amino-5-phenylchroman.hydrochloride

(R)-3-(N-propyl)amino-5-phenylchroman (0.46 g, 1.74 mmol) was dissolvedin methanol (15 mL). Formaldehyde (0.70 g, 8.70 mmol) was added and thereaction vessel was cooled on an ice bath. Sodium cyanoborohydride (0.58g, 9.23 mmol) was added in portions which after pH was adjusted to pH 6with a few drops of conc. acetic acid. The reaction mixture was stirredat room temperature for 3 hours. The solvent was evaporated and theresidue was partitioned between ether (50 mL) and 1M NH₃ -solution (10mL). The layers were separated and the aqueous phase was extracted withether (50 mL). The combined organic layers were washed with 1M NH₃-solution (10 mL), dried (MgSO₄), filtered and evaporated. The residuewas purified by column chromatography (eluent: hexane: EtOAc 70:30+0.1%conc. NH₃) yielding 0.40 g (81%) of the corresponding base of the titlecompound as an uncoloured oil which solidified upon standing: [α]²¹=-35.9 (c=1.0, MeOH). Conversion to the hydrochloride was done inHCl/ether giving 0.4 g (total yield: 75%) of the title compound Mp162°-164° C.

Example 71 (R)-3-[N-2-(2-thienyl)ethyl]amino-5-phenylchromanhydrochloride

To a solution of (R)-3-amino-5-phenylchroman (0.41 g, 1.83 mmol) in dryDMF (2.0 mL) were added K₂ CO₃ (0.28 g, 2.02 mmol) and2-(2-thienyl)ethyl bromide (0.36 g, 1.80 mmol). The reaction mixture wasstirred under N₂ at 65° C. for 6 hours. The solvent was removed in vacuoand the residue was partitioned between ether (50 mL) and 1M NH₃-solution (10 mL). The layers were separated and the aqueous phase wassaturated with NaCl (s) and extracted with an additional amount of ether(25 mL). The organic layers were combined, dried (MgSO₄), filtered andconcentrated. The residue was purified by column chromatography (eluent:hexane: EtOAc 65:35+0.2% conc. NH₃) giving 0.19 g (31%) of thecorresponding base of the title compound as a light yellow oil: [α]²¹=+8.2 (c=1.0, MeOH). Conversion to the hydrochloride was done inHCl/ether giving 0.20 g (total yield: 29%) of the title compound: mp191.6°-193.2° C.

Example 72 3-Dipropylamino-8-fluoro-5-trifluoromethanesulfonyloxychroman

a) 2-Fluoro-5-methoxybenzoic acid

The title compound was prepared according to a method reported by Hayand Blanchard [Canad. J. Chem. 43, 1306 (1965)]. In a three-neckedround-bottom flask (1000 mL), equipped with a magnetic stirrer,thermometer, reflux condensor and a gas distribution tube,cobalt(II)acetate tetrahydrate (12.6 g; 51 mmol) was dissolved inglacial acetic acid (404 mL) by stirring. Commercial4-fluoro-3-methylanisole (35.4, 252 mmol) and 33% HBr in acetic acid(10.1 mL; 51 mmol) were added and then the mixture was heated on anoil-bath to 90°-95° C. All the time a stream of oxygen was passedthrough the solution at a rate of about 660 mL/min. After 3 hours thereaction mixture was cooled to room temperature and then rotaryevaporated to dryness.

The violet colored solid thus obtained was transferred to an Erlen-Meyerflask, dissolved in boiling water (350 mL) containing concentratedhydrochloric acid (5-10 mL) and then allowed to crystallize at a coldplace over night. The crude acid was filtered off by suction, washedwith small portions of ice-water until the washing were pale yellow,dissolved in 2M NaOH (120 mL) and washed with toluene (2×100 mL). Theorganic extracts were discarded. The aqeous phase was suction filtered,cooled in a beaker on an ice-bath and carefully acidified withconcentrated hydrochloric acid until all the acid was precipitated. Thecontents in the beaker was heated to the boiling oint whereby most ofthe acid dissolved. The solution was cooled at room temperature andfinally in the refrigerator. The mother liquor was sucked off. Thecrystal mass was washed with ice-water (3×50 mL) and then dried in avacuum-oven at 40° C. to give 31.5 g of the title compound as agrey-white solid. Mp. 146°-148° C.

b) 2-Fluoro-5-methoxybenzamide

In a three-necked round-bottom flask (500 mL), equipped with a magneticstirrer and a reflux condensor, 2-fluoro-5-methoxybensonic acid (33.8 g;199 mmol) and thionyl chloride (200 mL) were refluxed under nitrogen for2 h. The excess of thionyl chloride was evaporated to leave an oilyresidue which was dissolved in methylene chloride (100 mL) andevaporated. This procedure was repeated three times. The crude acidchloride thus obtained was dissolved in methylene chloride (100 mL) andadded dropwise during 10 min to a cold (-40° to -50° C.) andmechanically stirred solution of dry THF (300 mL) and liquid ammonia(100 mL) in a three-necked round-bottom flask (1000 mL) under nitrogen.When the addition was completed the cooling bath was taken away and themixture was slowly warmed to room temperature while the stirring wascontinued. Water (50 mL) was added to dissolve the precipitated salt andthe two-phase solution obtained was concentrated to dryness byrotary-evaporation. The crude amide was washed repeatedly with smallportions of dilute aqueous ammonia followed by water until the washingswere colourless. Drying at reduced pressure over night afforded 32.0 gof the title compound as light-brown crystals. Mp. 122°-124° C.

c) 2-Fluoro-5-methoxyaniline

In a round-bottom flask (500 mL), equipped with a reflux condensor and amagnetic stirrer, bromine (11.4 mL; 223 mmol) was added dropwise to acold (+4° C.) and stirred solution of sodium hydroxide (35.5 g; 887mmol) and water (322 mL). Then 2-fluoro-5-methoxybenzamide (31.9 g; 189mmol) was added in portions. The mixture was heated on an oil-bath,refluxed for 1 h, cooled to room temperature and extracted with ether(3×300 mL). Drying the combined ether phases (K₂ CO₃), filtering,evaporation of the solvent and vacuum distillation of the oily residueafforded 20.1 g of the title compound as a pale yellow oil (bp.113°-114° C. /14 mmHg), which solidified in the cold (Mp. 27°-28° C.).

d) 2-Fluoro-5-methoxyphenol

The method used to prepare the phenol is basically the procedurereported by Claudi et. al. [med. Chem. 33, 2408-2412 (1990) withmodification according to Lambooy [J. Amer. Chem. Soc. 72, 5327-5328(1950)]. In a three-necked round-bottom flask (1000 mL), equipped withdropping-funnel and a magnetic stirrer, 2-fluoromethoxyaniline (11.3 g,80 mmol ), concentrated sulfuric acid (35 mL) and water (200 mL) weremixed and then cooled to 3°-5° C. A solution of sodium nitrite (6.07 g;88 mmol) in water (20 mL) was added dropwise to the stirred mixtureabove at 2°-4° C. When the addition was completed the solution wasstirred for five minutes and then urea (0.48 g) was added followed bywater (100 mL). Meanwhile an apparatus was prepared consisting of athree-necked round-bottom flask (1000 mL), a thermometer, an electricalheating mantle, a steam distillation apparatus, and long (40 cm)water-jacketed condensor on top of which a 500 mL dropping funnel wasattached. In the flask CuSO₄ ×5H₂ O (56 g), concentrated sulfuric acid(160 mL) and water (160 mL) were placed. The mixture was heated to 150°C., the diazonium salt solution, cooled all the time by adding smallchunks of the ice to it, was added dropwise from the dropping funnel,and a current of steam was passed through the system to remove thephenol. The distillate was extracted with ether (3×400 mL) and thecombined ether extracts were dried (MgSO₄), filtered and concentrated invacuo. The crude phenol was purified on a silica column eluted withether/n-hexane (15:85) to afford 4.03 g of the title compound as acrystalline solid. Mp. 25°-26° C.

e) 3-Cyano-8-fluoro-5-methoxy-2-H-chromen

The synthesis of the title compound is based on a method reported byThorberg et. al. in Acta Chem Scand. 24, 169-182 (1987). Trichloroaceticacid (approx. 0.04 g) was added to a stirred solution of2-fluoro-5-methoxyphenol (6.8 g, 48 mmol) and ethyl vinyl ether (9.1 mL,95 mmol) under nitrogen in a round-bottom flask (50 mL) at +4° C. Themixture was stirred at room temperature over night. Excess ethyl vinylether was rotary-evaporated and the residue dissolved in ether (100 mL).The ether solution was washed with saturated Na₂ CO₃ (2×5 mL), dried K₂CO₃), filtered and concentrated in vacuo. The oily residue was dissolvedin dry toluene (100 mL) and the solution was concentrated, first using arotary-evaporator and then a vacuum-pump (0.1 mmHg), to afford 10.0 g ofthe protected phenol as yellow oil. In a dry three-necked round-bottomflask (100 mL), equipped with a magnetic stirrer and a rubber septum,8.8 g (41 mmol) of the protected phenol form above was dissolved in dryTHF (30 ML) under nitrogen. The solution was cooled to -25° C. on a dryice-bath. Then 1.6M. n-BuLi in hexane (32 mL; 51 mmol) was addeddropwise with a syringe to the stirred solution duting 15 min. When theaddition was completed the mixture was warmed to -15° C. In 1 h, thencooled to -20° C. Dry dimethylformamide (4.7 mL; 60 mmol) was addeddropwise during 5 min while the temperature was kept at -25° to -20° C.(the reaction is exothermic). When the addition was completed thesolution was warmed to -5° C. In 2 hours and then poured in ice-cold 2Mhydrochloric acid (200 mL). After stirring for 40 min the hydrolysis wascomplete as seen from TLC. The resulting mixture was washed with ether(3×250 mL). The combined ether phases were dried (MgSO₄), filtered andconcentrated in vacuo. The yellow solid residue was dissolved in ether(50 mL) and concentrated to afford 7.12 g of crude3-fluoro-2-hydroxy-6-methoxybenzaldehyde as a yellow crystalline solid.

Crude 3-fluoro-hydroxy-6-methoxybenzaldehyde (8.0 g) from above,acrylonitrile (13 mL; 193 mmol) and 1.4.diazadicyclo [2,2,2] octane(0.66 g; 5.9 mmol) were refluxed in a three-necked round-bottom flask(50 mL) under nitrogen for 4 h. Rotary-evaporation of the volatiles lefta thick, red oil which was flash-chromatographed on a silica columneluted with methylene chloride/n-hexane (4:5). Concentration of relevantfractions gave an impure product (91% GC) which was crystallized formEtOAc to give 1.31 g of the title compound as colourless bars. Mp.133°-135° C.

f) 8-Fluoro-5-methoxychroman-3-yl carboxylic acid

3-Cyano-8-fluoro-5-methoxy-2-H-chromen (1.23 g; 6.0 mmol) and 2M sodiumhydroxide solution (25 mL) were refluxed under nitrogen for 7.5 hoursand then stirred at room temperature over night. Excess concentratedhydrochloric acid was added to the solution with stirring. After coolingthe slurry on an ice-bath, the precipitated carboxylic acid was suckeddry, transferred to a 250 mL hydrogenation flask (Parr) and dissolved inglacial acetic acid (110 mL). Palladium (5%) on activated carbon (0.104g was added. Hydrogenation in a Parr-apparatus at 1 atm hydrogenpressure and 40°-50° C. (IR-lamp) for 10 hours completed reaction. Thesuspension was filtered through Celite and filtrate was concentrated invacuo. The residue was dissolved in toluene (25 mL) and the solution wasconcentrated by rotary-evaporation. This procedure was repeated once.Evaporation with vacuum pump (0.05 mmHg) afforded 1.12 g of the titlecompound as grey-white solid. Mp. 140°-145° C. (decomp).

g) 8-Fluoro-5-methoxychroman-3-y-carbamic acid benzyl ester

8-Fluoro-5-methoxychroman-3-yl carboxylic acid (1.12 g; 85.0 mmol),diphenyl phosphoryl azide (1.3 mL; 5.9 mmol) and toluene (10 mL) weremixed in a three-necked round-bottom flask (50 mL) under nitrogen.Triethylamine (0.83 mL; 5.9 mmol) was added and clear solution wasstirred at 100° for 2 h. Benzylalcohol (0.61 mL; 5.9 mmol) was added inone portion and the stirring continued at 90° C. for 17 h. The volatileswere evaporated and the residue was taken up in toluene (25 mL). AfterWashing with 10% acetic acid (1×30 mL) and 2M ammonia (1×30 mL) thesolution was dried (MgSO₄), filtered and concentrated in vacuo to give abrown oil. Flash-chromatography of the crude product on a silica columneluted with ethyl acetate/toluene (3:97) afforded compound as an oil(contaminated with 2% unreacted isocyanate according to GC).

h) 3-Amino-8-fluoro-5-methoxychroman

8-Fluoro-5-methoxychroman-3-yl carbamic acid benzyl ester (1.37 g; 4.0mmol), absolute ethanol (90 mL), glacial acetic acid (10 mL) and 5%palladium on activated carbon (0.090 g) were mixed in a 250 mLhydrogenation flask (Parr). Hydrogenation in a Parr-apparatus at 1 atmhydrogen pressure and 45° C. (IR-lamp) over night completed the reaction(hydrogen uptake of 80 mL at 20° C.). The suspension was filteredthrough Celite and the filtrate was concentrated by rotary-evaporation.The residue was dissolved in toluene (25 mL) and concentrated again.This procedure was repeated once. Evaporation with a vacuum pump (0.05mmHg) gave 1.20 g of a wet crystal mass consisting mainly (93% GC) ofthe title compound (as the acetate).

i) 3-Dipropylamino-8-fluoro-5-methoxychroman

In a round-bottom flask equipped with a magnetic stirrer were placed thecrude acetate of 3-amino-8-fluoro-5-methoxychroman (1.18 g; approx. 3.9mmol) from above, dry methanol (10 mL), propanal (2.8 mL; 39 mmol),glacial acid (pH 3-4) and sodium boronhydride (0.25 g; 3.9 mmol) butwith no molecular sieves. The reaction mixture was stirred undernitrogen at room temperature for 1 h. The solution was filtered throughCelite and the solvent was evaporated to leave a liquid residue which,was diluted with water (25 mL) and extracted with ether (2×100 mL) afteradjusting pH to 10-11 with 5M sodium hydroxide. The collected etherphases were dried (K₂ CO₃), filtered and concentrated in vacuo.

Flash-chromatography of the crude on a silica column eluted with ethylacetate (2% and 10%) in n-hexane afforded 0.235 g of the title compoundas a colourless oil.

j) 3-Diproprylamino-8-fluoro-5-hydroxychroman hydrochloride

The hydrochloride salt of 3-dipropropylamino-8-fluoro-5-methoxychromanwas prepared by adding an excess of hydrochloride in ether to a stirredand cooled (+4° C.) solution of the base (0.235 g; 0.84 mmol) in ether(10 mL), then isolating the precipitated salt and drying it in avacuum-oven at 50°.

In a three-necked round-bottom flask (25 mL) equipped with a magneticstirrer and a rubber septum the salt from above was dissolved inmethylene chloride (7 mL) under nitrogen. The solution was cooled on adry ice-bath to -40° C., then boron tribromide (0.158; 1.7 mol) inmethylene chloride (1 mL) was added slowly with syringe to the stirredsolution. When the addition was completed (2 min) the temperature of thesolution was slowly raised to +4° C. and kept at that temperature withan ice-bath. After a total reaction time of 7 hours the solution waspoured in saturated sodium hydrogen carbonate (20 mL). The mixture wasextracted with ether (3×30 mL) and the collected ether phases werewashed with brine, dried (Na₂ SO₄), filtered and concentrated in vacuo.Flash-chromatography of the crude product on a silica column eluted withethyl acetate/n-hexane (15:85) afforded 0.195 g of3-dipropylamino-8-fluoro-5-hydroxychroman as an oil.

The title compound was prepared by precipitating the base with an excessof hydrochloride in ether and drying the salt thus obtained in avacuum-oven at 50° C. for 5 h. Yield 0.220 g (99% form the base), withwhite aomorphus solid. Mp. 190°-192° C.

k) 3-Dipropylamino-8-fluoro-5-trifluoromethane sulfonyloxychroman

In a dry three-necked round-bottom flask (25 mL) equipped with amagnetic stirrer and a rubber septum3-dipropylamino-8-fluoro-5-hydroxychroman hydrochloride (0.211 g; 0.70mmol), 2,4,6-collidine (0.110 mL; 0.84 mmol) and methylene chloride (7.3mL) were mixed under nitrogen. The clear solution was cooled to -40° C.on a dry ice-bath, then trifluoromethanesulfonic anhydride (0.230 mL;1.37 mmol) in methylene chloride (0.3 mL) was added slowly (5 min) tothe stirred mixture with a syringe. When the addition was completed thesolution was stirred for 1 hour (the temperature increased to 0° C.),then poured in cold (+4° C.) saturated sodium hydrogen carbonate (20 mL)and extracted with ether (2×40 mL). The collected ether phases werewashed with water (1×30 mL), dried (Na₂ SO₄), filtered and concentratedby in vacuo. The crude product was flash-chromatographed on a silicacolumn with ethyl acetate/n-hexane (1:19) to afford 0.213 g of the titlecompound as an oil.

Example 73 3-Dipropylamino-8-fluoro-5-(2-furyl)chroman hydrochloride

In a three-necked round-bottom flask (25 mL) equipped with a magneticstirrer and a reflux condensor the following reagents were mixed undernitrogen: 3-dipropylamino-8-fluoro-5-trifluoromethanesulfonylchroman(0.104 g; 0.25 mmol), absolute ethanol (1.7 mL), toluene (3.6 mL),2-furylboronic acid (0.071 g; 0.64 mmol), lithium chloride (0.022 g;0.51 mmol), 2M sodium carbonate (0.7 mL) andtetrakis(triphenylphosphine)palladium(0) (0.0073 g). The mixture washeated on an oil-bath to a reflux temperature (75°-80° C.). After 3hours GC-analysis indicated a partial reaction (20% product and 66%starting material). Therefore more 2-furylboronic acid (0.031 g; 0.28mmol), absolute ethanol (0.2 mL) andtetrakis(triphenylphosphine)-palladium(0) (0.009 g) were added. Themixture was stirred at 75°-80° C. over night, then poured in 2M ammonia(40 mL) and extracted with ether (2×40 mL). The collected ether phaseswere dried (Na₂ SO₄), filtered and concentrated in vacuo. The crudeproduct was purified by flash-chromatography on a silica column withethyl acetate/n-hexane (2:98). Relevant fractions were pooled andconcentrated to give an oil consisting of impure product (72% GC). Thismaterial was purified in a second run by flash-chromatography on asilica column eluted with eluted with ethyl acetate/methylene chloride(1:99) to give 0.042 g (51% yield) of3-dipropylamino-8-fluoro-5-(2-furyl)chroman as an oil.

The title compound was prepared from the base as described for3-dipropylamino-8-fluoro-5-hydroxychroman hydrochloride above. Whitecrystalline solid. Mp. 162°-164° C.

Example 74 3-Dipropylamino-8-fluoro-5-N-isopropylcarbamoylchromanhydrochloride

In a three-necked round-bottom flask (25 mL), equipped with a magneticstirrer and an inlet for carbon monoxide from a hydrogenation burette,dioxane (1.3 mL),3-dipropylamino-8-fluoro-5-trifluoromethanesulfonyloxychroman (Example63 k) 0.110 g; 0.20 mmol) and isopropylamine (0.118 mL; 1.4 mmol) weremixed. The flask was evacuated and the filled with carbon monoxide. Thisprocedure was repeated twice. 1,3-Bis(diphenylphosphino)propane (0.0032g) and palladium(II)acetate (0.0016 g) were added and then the mixturewas stirred at 75° C. under an atmosphere of carbon monoxide at 1 atm.GC-analysis showed that the reaction was unexpectedly slow. Stirringover night did improve the yield of desired product (59% GC) but stillmuch triflate was left (27% GC). Accordingly, more1,3-bis(diphenyl)phosphino)propane (0:0065 g) and palladium acetate(0.0032 g) were added. Unfortunately, stirring over night did notimprove the yield but rather resulted in some decomposition of theproduct as seen from GC. At this point the reaction was worked up byadding saturated sodium hydrogen carbonate (5 mL) and extracting themixture with ethyl acetate (2×10 mL). The combined organic phases weredried (Na₂ SO₄), filtered and concentrated in vacuo. The crude productwas flash-chromatographed on a silica column eluted with ethyl acetate(15 and 33%) in n-hexane to afford 0.021 g of starting material(triflate) and 0.030 g (40% yield based on recovered triflate) of3-dipropylamino-8-fluoro-5-N-isopropylcarbamoylchroman as an oil.

The title compound was prepared from the base as described for3-dipropylamino-8-fluoro-5-hydroxychroman hydrochloride above. Whitesolid. Mp. (70 eV); m/z (rel.int.), 337(4.4, M+1), 336(17,M), 308(21),307(100), 236(36), 194(6), 177(6), 43(19).

Example 75(R)-8-Fluoro-3-(N-isopropyl-N-propylamino)-5-trifluoromethanesulfonylchroman

(R)-8-Fluoro-3-(N-isopropyl-N-propylamino)-5-hydroxychroman (0.71 g,2.66 mmol) and collidine (0.49 mL, 3.72 mmol) were dissolved in 25 mL ofCH₂ Cl₂ and cooled to -40° C. Trifluoromethanesulfonic anhydride (0.54mL, 3.2 mmol) was added dropwise and allowed to warm to ambienttemperature, and after coming to 0° C. the reaction was done.

The reaction was diluted with CH₂ Cl₂ and washed with saturated NaHCO₃,dried (Na₂ SO₄), filtered, and evaporated in vacuo to give crude.

Chromatography on silica (eluent: CH₂ Cl₂) gave 0.82 g (77% yield) ofthe title compound as a clear oil. [α]²¹ -81.5° (C=0.1, CHCl₃).

Example 76 (R)-5-Acetyl-8-fluoro-3-(N-isopropyl-N-propylamino)chromanHydrochloride

(R)-8-Fluoro-3-(N-isopropyl-N-propylamino)-5-trifluoromethanesulfonylchroman(403 mg, 1.01 mmol) was dissolved in 3 mL DMF and then triethylamine(0.28 mL, 2.02 mmol), butyl vinyl ether (0.78 mL, 6.06 mmol), palladiumacetate (7 mg), and 1,3-bis-diphenylphospinopropane (14 mg) were added.The resulting mixture was heated to 80°-90° C. with stirring for 3.5 h.

The solution was cooled and 5 mL of a 2M HCl solution was added and thereaction was stirred at room temperature for 1 h.

The mixture was diluted with ether and washed with a 2M NH₃ solution.The aqueous phase was re-axtracted with ether and the combined etherphases were treated with brine, dried (MgSO₄), filtered, and evaporatedin vacuo to give a brown orange oil as crude.

Chromatography on silica (eluent: 15% EtOAc/hexane) gave 201 mg as ayellow oil (68% yield). [α]²¹ -165.1 (C=0.1, CHCl₃).

The HCl salt was precipitated from ether and recrystallized fromEtOAc/ether to give a white solid Mp 148° C.

Example 77 (R)-5-Phenyl-8-fluoro-3-(N-isopropyl-N-propylamino)chromanHydrochloride

To a solution of(R)-8-fluoro-3-(N-isopropyl-N-propylamino)-5-trifluoromethanesulfonylchroman(0.58 g, 1.45 mmol), ethanol (7 mL), lithium chloride (124 mg, 2.9mmol), 2M sodium carbonate (2.2 mL), andtetradis(triphenylphosphine)palladium(0) (31 mg, 0.026 mmol) dissolvedin toluene (15 mL) was phenylboronic acid (0.22 g, 1.74 mmol) added inone portion under nitrogen. The resulting solution was heated to 95° C.for 5 hours then the reaction was allowed to cool. The reaction wasfiltered and the solvent was evaporated in vacuo. The remains were takeninto ether, washed with 2M NH₃, treated with brine and dried (MgSO₄).Removal of the solvent in vacuo gave the crude compound.

Chromatography on silica (eluent: CH₂ Cl₂ +CH₂ Cl₂ +NH₃) gave 0.42 g(89% yield) of the title compound (base) as an oil. [α]²¹ -45.0 (C=0.1,CHCl₃).

The hydrochloride salt was made by dissolving the pure base in ether anddropping an excess of an ethereal HCl to give a white solid. Mp202°-203° C.

Example 78(R)-5-[Carbonyl(2,6-dimethylphenyl)]-8-fluoro-3-(N,N-dipropylamino)chromanHydrochloride

2-Bromo-m-xylene (0.5 mL, 3.6 mmol) was dissolved in 4 mL anhydrous THFunder nitrogen atmosphere and cooled to -78° C. n-Butyllithium (1.6M inhexane, 2.0 mL, 3.2 mmol) was added dropwise and the reaction wasallowed to stir at -78° C. for 1 hour.(R)-8-Fluoro-5-formyl-3-(N,N-dipropylamino)-chroman (0.30 g, 1.07 mmol)was dissolved in 5 mL anhydrous THF and added dropwise to the reactionmixture and then allowed to stir at -78° C. for 1 hour. The reaction wasquenched by adding 2 mL H₂ O and the reaction was allowed to warm toroom-temperature. The solvent was removed in vacuo, the remains weretaken into a 2M solution of NH₃ and then extracted thrice with ether.The combined ether portions were treated with brine, dried (MgSO₄),filtered, and the solvent removed in vacuo to give the crude alcohol asa white solid. A stream of nitrogen was gently allowed to blow on thecrude solid overnight to remove the excess 2-bromo-m-xylene. The crudealcohol was oxidized directly in the next reaction without furtherpurification.

Oxalyl chloride (122 μL, 1.4 mmol) was dissolved in 5 mL anhydrous CH₂Cl₂ under nitrogen atmosphere and cooled to -78° C. DMSO (0.24 mL, 3.4mmol) was added under 5 min then the reaction was allowed to stir at-78° C. for 5 min. The crude alcohol (from above) was dissolved in 10 mLanhydrous CH₂ Cl₂ and was added under 10 min to the reaction. Afterstirring at -78° C. for 25 min, triethylamine (0.75 mL, 5.4 mmol) wasadded and after 5 min the reaction was allowed to warm toroom-temperature. H₂ O/2M solution of NH₃ was added to the reaction andextracted thrice with CH₂ Cl₂. The combined CH₂ Cl₂ portions were dried(MgSO₄), filtered, and the solvent removed in vacuo to give the crudeketone. Chromatography on silica (eluent: 8.7% EtOAc/hexane) gave 345 mg(84% yield) of the title compound as a slightly yellow oil. [α]_(D) ²¹-57.0° (c 0.1, CHCl₃). Mass spectrum (70 eV) m/z (relative intensity)383(56M+), 354(100), 283(26), 355(36).

The hydrochloride salt was made by dissolving the pure base in ether anddropping an excess of an ethereal HCl. The salt was dried in a vacuumoven at 50° C. to give a white solid as a hemi-hydrate which sinters at80° C.

Example 79(R)-8-Fluoro-3-(N-isopropyl,N-n-propylamino)-5-(5-oxazolyl)chromanHydrochloride

(R)-8-Fluoro-5-formyl-3-(N-isopropyl,N-n-propylamino)chroman (0.48 g,1.7 mmol), tosylmethylisocyanide (0.37 g, 1.9 mmol) and K₂ CO₃ (0.28 g,2.0 mmol) were suspended in methanol (50 mL, dried 3 Å) undernitrogenatmosphere. The reaction mixture was refluxed for 1 hour.Diethyl ether and 2M NH₃ were added. The layers were separated and thewater phase was extracted twice with diethyl ether. The organic layerswere combined and dried (Na₂ SO₄). The solvent was removed in vacuo togive a colorless oily residue which was purified by flash chromatography(SiO₂, CH₂ Cl₂ /EtOAc, 10:1) to give the title compound in 60% yield(320 mg). [α]_(D) ²² -55° (c 5 mg/mL, MeOH). Mass spectrum (70 eV) m/z(relative intensity) 318(14,M+), 303(20), 290(12), 289(81), 191(11),149(12), 112(17), 85(23), 70(20), 56(20), 44(16), 43(100), 42(24),41(58), 30(11). The HCl salt was precipitated from diethyl ether andsinters from 80° C.

Example 80(R)-8-Fluoro-5-methoxycarbonyl-3-(N,N-di-n-propylamino)chroman

(R)-8-Fluoro-3-(N,N-di-n-propylamino)-5-trifloromethanesulfonyloxychroman(0.95 g, 2.4 mmol), triethylamine (0.53 g, 5.2 mmol),1,3-bis(diphenylphosphino)propane (100 mg, catalytic amount),palladium(II)acetate (50 mg, catalytic amount) and DMF/MeOH (18 mL, 6:2)were mixed in a 50 mL three necked round bottom flask. The flask wasevacuated followed by the inlet of CO (repeated three times). Thereaction mixture was stirred at 70° C. for 7 hours. The solvent wasremoved in vacuo and the residue was dissolved in diethyl ether/2M NH₃.The layers were separated and the water phase was extracted once withether. The combined ether layers were dried (MgSO₄) and the solvent wasremoved in vacuo to give a brown oily residue which was purified byflash chromatography (SiO₂, CH₂ Cl₂ /EtOAC, 20:1) to give 650 mg of thetitle compound as a clear oil (87% yield). [α]_(D) ²¹ -92° (c 10 mg/mLMeOH) Mass spectrum (70 eV) m/Z (relative intensity) 309(20, M+),281(18), 280(100), 56(10), 43(22), 42(12), 41(16).

Example 81 (R)-8-Fluoro-5-formyl-3-(N,N-di-n-propylamino)chroman

(R)-8-Fluoro-5-methoxycarbonyl-3-(N,N-di-n-propylamino)chroman (0.65 g,2.1 mmol) was dissolved in THF (30 mL, sodium dried) under nitrogenatmosphere. The solution was cooled to -78° C. beforediisobutylaluminium hydride (DIBAL-H, 1.0M, 8.4 mL, 8.4 mmol) was addedunder 10 min. The cooling bath was removed and the temperature of thereaction mixture was allowed to slowly raise to r.t. (20° C.). Thereaction mixture was stirred for 3 hours before the reaction wasquenched by the addition of 2M NaOH (2 mL). Saturated sodium tartrateand diethyl ether were added and the mixture was stirred until the "gel"dissolved. The layers were separated and the water phase was extractedtwice with ether. The combined organic layers were dried (MgSO₄) and thesolvent was removed in vacuo to give the alcohol.

Oxalyl chloride (0.30 g, 2.3 mmol) was dissolved in CH₂ Cl₂ undernitrogen atmosphere. The solution was cooled to -78° C. before DMSO (0.4g, 5.0 mmol) was added dropwise under 5 min. After stirring for 5 min,the alcohol, dissolved in CH₂ Cl₂, was added under a 30 min period. Thereaction mixture was stirred for 30 min before triethylamine (1.1 g,10.5 mmol) was added under a 5 minutes perion. The stirring wascontinued. After 130 minutes the cooling bath was removed and thereaction mixture was slowly warmed ut to r.t. and then stirred for anadditional 30 min before NaHCO₃ was added. The layers were separated andthe water phase was extracted twice with ether. The combined organiclayers were dried (MgSO₄) and the solvent was removed in vacuo to givean oily residue which was purified by flash chromatography (SiO₂, CH₂Cl₂ /EtOAc, 20:1) to give 350 mg of the title compound (60% yield).[α]_(D) ²¹ -86° (c 10 mg/mL MeOH). Mass spectrum (70 eV) m/z (relativeintensity) 279(5, M+), 250(56), 179(48), 151(13), 149(10), 123(31),103(28), 98(24), 77(11), 72(26), 70(44), 57(15), 56(54), 55(18), 54(16),44(11), 43(100), 42(64), 41(79).

Example 82(R)-5-[Carbonyl-(3,5-dimethylisoxazole)]-8-fluoro-3-(N,N-di-n-propylamino)chromanHydrochloride

4-Bromo-3,5-dimethylisoxazole (1.9 g, 10.7 mmol) was dissolved n THF (20mL, sodium dried) under a nitrogen atmosphere. The solution was cooledto -90° C. before n-butyllithium (1.6M in hexane, 9.7 mL, 9.7 mmol) wasadded under 10 min. The reaction mixture was stirred for 15 min before(R)-8-fluoro-5-formyl-3-(N,N-di-n-propylamino)chroman (0.6 g, 2.2 mmol),dissolved in THF (10 mL), was added under a 10 min period. The reactionmixture was stirred at -90° C. for an additional 20 min and then at -78°C. for 15 min before it was quenched by the addition of NH₄ Cl. Diethylether and 2M NH₃ were added. The layers were separated and the waterphase was extracted once with ether. The combined organic layers weredried (Na₂ SO₄). The solvent was removed in vacuo to give a yellow oilyresidue which was flushed overnight with a nitrogen stream. Oxalylchloride (0.28 g, 2,2 mmol) was dissolved in CH₂ Cl₂ under a nitrogenatmosphere. The solution was cooled to -78° C.

DMSO 0.38 g, 4.8 mmol) was added dropwise under a 5 min period. Thereaction mixture was stirred for 20 minutes before the crude alcohol,dissolved in CH₂ Cl₂ was added under 15 min. The reaction mixture wasstirred for 30 min. Triethylamine (1.01 g, 10 mmol) was added. Thestirring was continued for 1 hour before the cooling bath was removedand the reaction mixture was allowed to warm to r.t. (21° C.). Diethylether and NaHCO₃ were added. The layers were separated and thewater-phase was extracted once with ether. The combined organic layerswere dried (Na₂ SO₄) and the solvent was removed in vacuo to give ayellow oily residue which was purified by flash chromatography (SiO₂,CH₂ Cl₂ /hexane/EtOAc, 10:10:1) to give 340 mg of the title compound(42% yield). Mass spectrum (70 eV) m/z (relative intensity) 374(11,M+),346(21), 345(100), 274(15), 43(11). The HCl-salt was precipitated fromdiethyl ether at 0° C. and then recrystallized from CH₂ Cl₂ /diethylether. mp 202°-205° C.

Example 83 (R)-5-N-Morpholinyl-3-(N-isopropyl-N-n-propylamino)chromanHydrochloride

Diglycolic acid (0.15 g, 1.1 mmol) and N,N-carbonyldiimidazole (CDI,0.28 g, 1.8 mmol) were dissolved in THF (dried over sodium) undernitrogen atmosphere. The mixture was refluxed for 15 min before(R)-5-amino-3-(N-isopropyl-N-n-propylamino)chroman (NAE 277) (0.2 g, 0.8mmol) was added. The refluxing was continued for 18 hours. The reactionmixture was then combined with a similar reaction mixture from anidentical reaction (starting from 0.1 g of the aniline). Diethyl etherand 2M NH₃ were added. The layers were separated and the water phasewase extracted once with ether. The combined organic layers were dried(Na₂ SO₄) and the solvent was removed in vacuo to give an ioly residue.The residue was dissolved in diethyl ether under nitrogen atmosphere.Lithium aluminium hydride (0.23 g, 6 mmol) was added and the mixture wasrefluxed for 18 hours. Water (0.3 mL) followed by 0.3 mL of 15% NaOH andfinally 1 mL of water was added under vigorous stirring.

The solution was decanted from the white solid residue and the residuewas washed twice with ether. The organic layers were combined and thesolvent was removed in vacuo to give the crude residue which waspurified by flash chromatography (SiO₂, CH₂ Cl₂ /EtOAc, 5:1, alsocontaining 0.5% of NH₃) to give 180 mg of the title compound (47%yield). [α]_(D) ²¹ -39° (c 5 mg/mL MeOH). Mass spectrum (70 eV) m/z(relative intensity) 318(8,M+), 133(14), 130(13), 117(10), 114(32),112(45), 85(28), 43(100), 42(27), 41(44), 39(23). The HCl salt wasprecipitated from diethyl ether and recrystallized from EtOAc/diethyl.The crystalls sinters from 70° C.

Example 84 (R)-5-Carbamoyl-2-aminochroman

a) (R)-5-Carbamoyl-2-N-Trifluoroacetylaminochroman

(R)-2-N-Trifluoroacetylamino-5-trifluoromethanesulfonyloxychroman (2.0g, 5.0 mmol) was dissolved in DMF (20 mL) in a three necked roundbottomflask. The flask was evacuated followed by inlet of CO-gas (repeatedthree times). 1,3-Bis(diphenylphosphino)-propane (0.2 g, catalyticamount), palladium(II)acetate (0.1 g, catalytic amount) and dioxanesaturated with NH₃ (20 mL) were added before the reaction mixture wasstirred at 70° C. for 8 hours. The solvent was removed in vacuo. Theresidue was dissolved in diethyl ether/NH₃ (2M). The layeres wereseparated and the water phase was extracted twice with diethyl ether.The combined organic layers were dried (MgSO₄). The solvent was removedin vacuo to give an orange oily residue which was purified by flashchromatography [SiO₂, CH₂ Cl₂ :EtOAc,4:1 (+0.5% of NH₃)] to give thetitle compound in 21% yield (0.30 g). Mp 178°-180° C. Mass spectrum (70eV) m/z (relative intensity) 288(5, M+), 176(11), 175(100), 174(22),158(13), 131(25), 130(42), 51(19), 44(16).

b) (R)-5-Carbamoyl-2-aminochroman

(R)-5-Carbamoyl-2-N-trifluoroacetylaminochroman (0.30 g, 1.04 mmol) wasdissolved in CH₂ Cl₂ (50 mL). Sodium hydroxide (5 mL of 15% in water)was added and the mixture was stirred for 4 hours. The layers wereseparated and the water phase was extracted with CH₂ Cl₂ four times. Theorganic layers were combined and the solvent was removed in vacuo togive a solid residue which was suspended in diethyl ether (300 mL) andfiltered. The ether was removed in vacuo to give the title compound in90% yield (180 mg). mp 194°-196° C. [α]_(D) ²¹ -36° (MeOH, c 10 mg/mL).Mass spectrum (70 eV) m/z (relative intensity) 192(1, M+), 176(26),175(100), 160(13), 130(14), 51(22), 44(13), 43(83), 42(15).

Example 85 (R)-2-N,N-Dibenzylamino-5-methoxycarbonylchroman

a) (R)-2-N,N-dibenzylamino-5-methoxy-chroman

(R)-5-Methoxy-2-aminochroman (2.6 g, 14 mmol), K₂ CO₃ (7.0 g, 51 mmol),benzyl bromide (6.0 g, 35 mmol) and a catalytic amount of KI were mixedin acetonitrile (100 mL) under a nitrogen atmosphere. The reactionmixture was stirred at 85° C. for about 72 hours. The solvent wasremoved in vacuo and the residue was dissolved in diethyl ether/NH₃(2M). The layers were separated and the water phase was extracted twicewith diethyl ether. The ether layers were combined and dried (MgSO₄).The solvent was removed in vacuo to give a yellow oily residue which waspurified by flash chromatography (SiO₂ n CH₂ Cl₂) to give the titlecompound in 64% yield (3.2 g). The HCl salt was precipitated fromdiethyl ether at 0° C. and then recrystallized from EtOH/diethyl ether.The crystalls are hygroscopic and starts to melt very slowly from 100°C. and melt finally between 118° and 120° C. [α]_(D) ²¹ -20° (c 33mg/mL, the HCl salt in MeOH). Mass spectrum (70 eV) m/z (relativeintensity) 360(19), 359(91,M+), 268(16), 223(11), 210(15), 132(72),91(100).

b) (R)-2-N,N-Dibenzylamino-5-hydroxy-chroman

(R)-2-N,N-Dibenzylamino-5-methoxychroman hydrochloride (1.6 g, 4.0 mmol)was dissolved in CH₂ Cl₂ (40 mL) under a nitrogen atmosphere. Thesolution was then cooled to -70° C. BBr₃ dissolved in CH₂ Cl₂ (25 mL)was added dropwise under a 5 minutes period. The reaction mixture wasthen warmed up slowly to 0° C. and stirred at that temperature overnight. The reaction mixture was slowly poured into a stirred saturatedsolution of NaHCO₃. The layers were separated and the water phase wasextracted three times with CH₂ Cl₂. The organic layers were combined anddried (MgSO₄). The solvent was removed in vacuo to give a brownish oilyresidue which was purified by flash chromatography (SiO₂, CH₂ Cl₂) togive the title compound in 98% yield (135 mg). [α]_(D) ²¹ -94° (c 10mg/mL, MeOH). Mass spectrum (70 eV) m/Z (relative intensity) 346(26),345(100), 132(13), 91(11).

c) (R)-2-N,N-Dibenzyl-5-trifluoromethanesulfonyloxychroman

(R)-2-N,N-Dibenzylamino-5-hydroxychroman (1.5 g, 4.3 mmol) and collidine(0.6 g, 5.2 mmol) were dissolved in CH₂ Cl₂ (30 mL) under a nitrogenatmosphere. The solution was cooled to -70° C. andtrifluoromethanesulfonic anhydride (1.3 g, 4.7 mmol), dissolved in CH₂Cl₂ (20 mL), was added dropwise during a 10 minutes period. The coolingbath was removed and the reaction mixture was slowly warmed up to roomtemperature (21° C.). The reaction mixture was washed with NH₃ (2M) anddried (MgSO₄). The solvent was removed in vacuo to give an orange solidresidue which was purified by flash chromatography (SiO₂, CH₂ Cl₂) togive the title compound in 90% yield (1.85 g). [α]_(D) ²¹ -83° (c 20mg/mL, MeOH). Mass spectrum (70 eV) n/z (relative intensity) 477(14,M+), 345(25), 344(100), 132(31, 91(78).

d) (R)-2-N,N-Dibenzylamino-5 methoxycarbonylchroman

(R)-2-N,N-Dibenzylamino-5-trifluoromethanesulfonyloxychroman (1.8 g, 3.8mmol) and triethylamine (0.8 g, 8.3 mmol) were dissolved in a solutionof DMF/MeOH (20 mL, 6:2) in a three necked round bottom flask. The flaskwas evacuated, followed by inlet of CO gas (repeated three times).Palladium(II)acetate (28 mg, catalytic amount) and1,3-bis(diphenylphosphino)-propane (60 mg, catalytic amount) were addedand the reaction mixture was stirred at 75° C. for 6 hours. The solventwas removed in vacuo to give a brownish oily residue. The oil wasdissolved in diethyl ether/NH₃ (2M). The layers were separated and thewater phase was extracted once with diethyl ether. The combined etherlayers were dried (MgSO₄). The solvent was removed in vacuo to give abrown oily residue which was purified by flash chromatography (SiO₂, CH₂Cl₂ /hexane, 1:1) to give the title compound in 95% yield (1.4 g).[α]_(D) ²¹ -147° (c 5 mg/mL, MeOH). Mass spectrum (70 eV) m/z (relativeintensity) 388(25), 387(100, M+), 297(10), 296(62), 264(27), 132(40),91(79).

Example 86 (R)-5-Carbamoyl-2-N,N-dibenzylchroman

(R)-2-N,N-Dibenzylamino-5-methoxycarbonylchroman (1.4 g, 3.6 mmol) wasdissolved in MeOH (20 mL). A solution of NaOH (0.16 g, 4.0 mmol) inwater (6 mL) was added and the reaction mixture was refluxed over night.The solvent was removed in vacuo. Toluene was added and the solvent wasremoved again (repeated twice in order to remove the water). The residuewas dissolved in SOCl₂ (6 mL) and refluxed for 1 hour. The solvent wasremoved in vacuo. The residue was dissolved in CH₂ Cl₂ (20 mL) and NH₃-gas was flushed through the solution for 2 minutes. The reactionmixture was stirred at r.t. for 1 hour before washing (2M NH₃) and dried(MgSO₄). The solvent was removed in vacuo to give a crude brownish oilyresidue which was purified by flash chromatography [SiO₂, CH₂ Cl₂/EtOAc, 5:1(+0.5% of NH₃)] to give the title compound in 41% yield (0.55g). [α]_(D) ²¹ -129° (c 10 mg/mL, MeOH). Mass spectrum (70 eV) m/z(relative intensity) 372 (2, M+), 281(43, 264(27), 132(19), 106(12),105(18), 91(100), 77(12), 65(25), 32(22).

Example 87(R)-5-[1-methyl(5-imidazolyl)]-3-(N-isopropyl-N-n-propylamino)chroman

(R)-5-Formyl-3-(N-isopropyl-N-n-propylamino)chroman (0.4 g, 1.5 mmol)was dissolved in methanol (15 mL), saturated with methylamine. Somemolcular sieves (3 Å) were added. The solvent was removed in vacuo. Theresidue was dissolved in methanol (30 mL) under nitrogen atmosphere.Tosylmethylisocyanide (0.36 g, 1.8 mmol) and K₂ CO₃ (0.25 g, 1.8 mmol)were added and the reaction mixture was reluxed for 1 hour. Additionallytosylmethylisocyanide (0.36 g, 1.8 mmol) and K₂ CO₃ (0.25 g, 1.8 mmol)were added and the reflux was continued for 3 hours.Tosylmethylisocyanide (0.1 g, 5.2 mmol) was added once more and thereflux was continued for 12 hours. The solvent was removed in vacuo. Theresidue was dissolved in diethyl ether/2M NH₃. The layers were separatedand the water-phase was extracted once more with ether. The organiclayers were combined and dried (Na₂ SO₄). The solvent was removed invacuo to give a brown oily residue which was purified by flashchromatography (SiO₂, first CH₂ Cl₂ /EtOAc, 5:1, also containing 0.5% ofNH₃ and then EtOAc/EtOH, 50:1+0.5% of NH₃) to give 200 mg of the titlecompound (42 yield). [α]_(D) ²¹ -37° (c 30 mg/mL, MeOH). The HCl-saltwas precipitated from diethyl ether at 0° C. and recrystallized fromethanol/diethyl ether. mp 159°-161° C. (dec).

Example 88(R)-3-(N-Isopropyl,N-n-propylamino)-5-(N-Isopropyl)carbamoylchroman.

a) (R)-3-(N-Isopropyl,N-n-propylamino)-5-methoxycarbonylchroman

(R)-3-(N-Isopropyl,N-n-propylamino)-5-trifluoromethanesulfonyloxychroman(4.0 g, 10.5 mmol), triethylamine (2.3 g, 23.1 mmol) and a mixture ofDMF/MeOH (18 mL, 6:2) was mixed in a three necked round-bottom flask.The flask was evacuated followed by inlet of CO-gas (repeated twotimes). Finally 1,3-bis(diphenylphosfino)propane (0.11 g, catalyticamount) and palladium(II)acetate (0.07 g, catalytic amount)) was addedbefore the mixture was stirred at 70° C. for 17 hours. The recationmixture was diluted with diethyl ether, washed with 2M NH₃ and dried(MgSO₄). Removal of solvent in vacuo gave a brown oily residue which waspurified by flash chromatography (SiO₂, CH₂ Cl₂ /EtOAc; 10:1) to givethe title compound in 82% yield (2.5 g). [α]_(D) ²¹ -131.6° (MeOH 0.1M,21° C.). Mp 125.5°-127.4° C. Anal. Calcd for C₁₇ H₂₆ O₃ NCl: C, 62.3; H,8.0; N, 4.3. Found: C, 62.5; H, 7.9; N, 4.4.

b) (R)-3-(N-Isopropyl,N-n-propylamino)-5-(N-Isopropyl)carbamoylchroman

(R)-3-N-(N-Isopropyl,N-n-propylamino)-5-methoxycarbonylchroman (0.46 g,1.6 mmol), dissolved in MeOH (10 mL), was mixed with a solution of NaOH(0.06 g, 1.6 mmol) in water (3 mL). The reaction mixture was thenrefluxed for 3.5 hours before the solvent was removed in vacuo. Theresidue was dissolved in toluene. The toluene was removed in vacuo(repeated two times) in order to form an azeotrope to remove the water.The carboxylic acid was then dissolved in SOCl₂ (5 mL) and refluxed for1 hour. The excess of SOCl₂ was removed in vacuo. The acid chloride wasthen dissolved in CH₂ Cl₂ (20 mL, dried with molecular sieves 3 Å)before 4 mL of isopropylamine was added. The reaction mixture wasstirred for 1 hour at room temperature (21° C.) before it was dilutedwith diethyl ether, washed (2M NH₃) and dried (MgSO₄). Removal ofsolvent in vacuo gave a yellow oily residue which was purified by flashchromatography (SiO₂, CH₂ Cl₂ /EtOAc; 5:2) to give the pure titlecompound in 88% yield (0.46 g). [α]_(D) ²¹ -90.4° (MeOH, 0.1M, 21° C.).Mp 92.5°-94° C.

Example 89(R)-8-Fluoro-3-(N-isopropyl-N-propylamino)-5-N-isopropylcarbamoylchroman

(R)-8-Fluoro-3-(N-isopropyl-N-propylamino)-5-trifluoromethanesulfonylchroman(0.405 g, 1.01 mmol) was dissolved in 4 mL dioxane and the solution wasdegassed (10 mmHg, RT, 5 min.) Then subjected to CO atmosphere.

Then palladium acetate (7 mg), 1,3-bis-diphenylphosphinopropane (12 mg),and isopropylamine (0.44 mL, 5.0 mmol) were added. The resultingsolution was again subjected to CO atmosphere and heated to 80° C. withstirring for 4 hours. The reaction was allowed to cool, filtered throughcelite, and the solvent was removed in vacuo to give the crude residue.

Chromatography on silica (eluent: 35% EtOAc/hexane) gave 0.24 g (71%yield) of the title compound as a clear oil that slowly crystallized. Mp56°-60° C. [α]_(D) ²¹ -82.2° (c 0.1, CHCl₃).

Example 90 (R)-8-Fluoro-3-(N,N-dipropylamino)-5-(N-methylcarbamoyl)chromanhydrochloride

A mixture of(R)-8-fluoro-3-(N,N-dipropylamino)-5-trifluoromethanesulfonylchromane(0.47 g), Pd(II)acetate (7 mg), 1,3-bis (diphenylphosphino)propane (14mg), methylamine (25 ml of 1M solution in dioxane) was stirred under acarbon monoxide atmosphere (1 atm) at 70° C. for 22 hours. Aqueous workup followed by column chromatography on silica (4% EtOH in CHCl₃) gave(R)-8-fluoro-3-(N,N-dipropylamino)-5-(N-methylcarbamoyl)chroman (0.20 g;55% yield) as an oil which crystallized. Mp. 72°-73° C. (fromether-hexane) [α]_(D) ²⁰ -92.1° (c 1.0, CHCl₃). Treating an etherealsolution of the base with an excess of HCl in ether gave the titlecompound as a white solid which was dried in vacuum at 60° C. Mp.85°-130° (sintered).

Example 91 (R)-3-(N-cyclopentyl,N-n-propylamino)-8-fluoro-5-methylcarbamoylchroman

a) (R)-3-N-cyclopentylamino-8-fluoro-5-methoxychroman

(R)-3-amino-5-methoxychroman (1.5 g, 7.6 mmol), acetic acid (0.45 g 7.6mmol), and cyclopentanone (2.5 g, 3 mmol) were dissolved in 30 ml ofmethanol. With stirring, sodiumcyanoborohydride (0.8 g, 13 mmol) wasadded in portions in a few minutes. Stirring was continued for 2 hours.A GC sample showed 100% of a new product. The solvent was evaporated andwater, 2 molar ammonia and EtOAc were added. The organic layer wasseparated and washed neutral with water. The layer was dried with Na₂SO₄ and evaporated to give 1.3 g (64% yield) of an colourless oil. GC/MSwith the molecular peak of 265 confirmed the title compound.

b) (R)-3-(N-cyclopentyl, N-n-propylamino)-8-fluoro-5-methoxychroman

(R)-3-N-cyclopentylamino-5-methoxychroman (1.3 g, 5 mmol), acetic acid(0.3 g, 5 mmol) and propionic aldehyde (1.5 g, 25 mmol) were dissolvedin 30 ml of methanol. With stirring, sodiumcyanoborohydride (0.8 g, 13mmol) was added in portions in a few minutes and stirring was continued.After 3 hours a GC sample showed 100% of a new product. The solvent wasevaporated and water, 2 molar NH₃ and EtOAc were added. The organiclayer was separated and washed neutral with water. The layer was driedwith Na₂ SO₄ and evaporated to give 1 g (65% yield) of an colourlessoil. GC/MS with the molecular peak of 307 confirmed the title compound.

c) (R)-3-(N-cyclopentyl, N-n-propylamino)-8-fluoro-5-hydroxychroman

(R)-3-(N-cyclopentyl,N-n-propylamino)-8-fluoro-5-methoxychroman (1 g, 5mmol) was dissolved in 25 ml of CH₂ Cl₂. An excess of etheric HCl wasadded to form the HCl salt. A solution of BBr₃ (4 g, 15 mmol) in 10 mlof CH₂ Cl₂ was prepared and added droppwise in 10 minutes with stirringon an ice-bath. The reaction mixture was allowed to reach roomtemperature during continued stirring for 6 hours and the mixture waspoured out into ice water and made alkaline by adding ammonia. Theorganic layer was separated, dried with Na₂ SO₄ and evaporated to afforda darkbrown oil. Chromatography (SiO₂, di-isopropylether and hexane 1+1)afforded 1.1 g of an colourless oil. The HCl salt was prepared from thebase and etheric HCl and rerystallized from acetonitrile to give 0.85 g(52% yield). Mp 220°-221° C.

d)(R)-3-(N-cyclopentyl,N-n-propylamino)-8-fluoro-5-trifluoromethylsulphonatechroman

(R)-3-(N-cyclopentyl,N-n-propylamino)-8-fluoro-5-hydroxy-chroman (0.7 g,3 mmol) was dissolved in 25 ml of CH₂ Cl₂ and triethylamine (0.3 g, 3mmol) was added. The solution of triphlate anhydride (1 g, 4 mmol) in 5ml of CH₂ Cl₂ was added dropwise in 10 min at (-20° C. Stirring wascontinued for further 1 hour. The reaction mixture was poured out intoice water and the pH was adjusted to 8 by addition of ammonia andextracted by ether. The organic layer was separated, dried with Na₂ SO₄and evaporated to afford a brown oil. Chromatography (SiO₂, CH₂ Cl₂+hexane, 1+3) afforded 0.5 g (44% yield) of a colourless oil. GC/MS withthe molecular pek of 425 confirmed the title compound.

e)(R)-3-(N-cyclopentyl,N-n-propylamino)-8-fluoro-5-methylcarbamoylchroman

(R)-3-(N-cyclopentyl,N-n-propylamino-8-fluoro-5-trifluoromethylsulphonatechroman(0.5 g, 1 mmol) was dissolved in 15 ml of 1,4-dioxane. Palladium IIacetate (10 mg), 1,3-bis (diphenylphosphino)-propane (20 mg), andmethylamin (0.15 g, 5 mmol) were added and the mixture was stirred incarbon monoxide atmosphere over night at 70° C. Evaporation andchromatography (SiO₂, diethyleter+hexane 1+3) afforded the finalcompound as a colourless oil. The HCl salt was prepared to give 0.24 g(65% yield) of white crystals. Mp 108° C.

Example 92(R)-5-Carbamoyl-8-Fluoro-3-(N-3-pentyl-N-n-propylamino)chroman

a) (R)-8-Fluoro-5-methoxy-3-(N-3-pentylamino)chroman

To a stirred solution of (R)-8-fluoro-5-methoxy-3-aminochroman (3.13 g,15.9 mmol) and 3-pentanone (2.2 ml, 20.8 mmol) in 100 ml dry MeOH, NaBH₃CN (1.31 g, 20.8 mmol) was added during 10 min. The pH was adjusted topH was adjusted to pH 6 with acetic acid and the solution was stirred atroom temp. After 18 hours, 3-pentanone (0.5 ml, 4.7 mmol) was added andthe solution was stirred at room temp. for 3 hours. Concentration andextraction with 100 ml 2M NH₃ and 2×250 ml EtOAc, drying of the combinedorganic phases (Na₂ SO₄) and evaporation gave a crude product that waspurified by flash chromatography on silica with hexane:EtOAC:NH₃,60:40:0.5, to give 3.75 g of(R)-8-fluoro-5-methoxy-3-(N-3-pentylamino)chroman as an uncolored oil.[α]_(D) ²² -25° (c 1.14 in MeOH).

b) (R)-8-Fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chroman

Sodiumcyanoborohydride (1.3 g, 20.7 mmol) was added during 10 min. to astirred solution of (R)-8-fluoro-5-methoxy-3-(N-3-pentylamino)chroman(3.69 g, 13.8 mmol) and propionaldehyde (5 ml, 69.3 mmol) in 100 ml dryMeOH. The pH was adjusted with acetic acid to pH 6. The solution wasstirred in room temp. for 18 hours and propionaldehyde (1 ml, 13.7 mmol)was added. After stirring at room temp. for 3.5 hours the solution wasconcentrated, and the residue was partitionated between 100 ml 2M NH₃and 200 ml ether. Extraction with 2×200 ml ether and drying of thecombined organic layers (Na₂ SO₄) gave after evaporation a crudeproduct. Purification by flash chromatography on silica withhexane:acetone 20:1 gave 4.03 g of(R)-8-fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chroman as anuncolored oil. [α]_(D) ^(>) -83° (c 1.08 in MeOH).

c) (R)-8-Fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chromanhydrochloride

(R)-8-Fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chroman (4.59 g,14.8 mmol) was dissolved in ether. HCl in ether was added to precipitatethe HCl-salt, and gave after drying 4.59 g of(R)-8-fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chromanhydrochloride as a white powder. Mp. 30°-50° C. (sinters).

d) (R)-8-Fluoro-5-hydroxy-3-(N-3-pentyl-N-n-propylamino)chroman

Demethylation was done by addition of BBr₃ (2.6 ml, 27.5 mmol) in 10 mldry CH₂ Cl₂ during 20 min., to a stirred, cooled solution (-70° C.) of(R)-8-fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chromanhydrochloride (4.44 g, 12.8 mmol) in 100 ml dry CH₂ Cl₂ under N₂atmosphere and dry conditions. The solution was stirred for 1 hour at-70° C., 1 hour at 0° C. and 1 hour at room temp. and was thereafterpoured into 80 ml saturated NaHCO₃ aq. under vigirous stirring. After0.5 hour the layers where separated and the aqueous phase was extractedwith 2×150 ml CH₂ Cl₂. The combined organic layers where dried (Na₂ SO₄)and evaporated. The crude product was purified by flash chromatographyon silica with a gradient of petroleumether-petroleumether: EtOAc, 4:1to give 3.72 g of(R)-8-fluoro-5-hydroxy-3-(N-3-pentyl-N-n-propylamino)chroman (NAG 134)as an yellow-brown oil. [α]_(D) ²² -85° (c 1.02 in MeOH).

e) (R)-8-Fluoro-5-hydroxy-3-(N-3-pentyl-N-n-propylamino)chromanhydrochloride

(R)-8-Fluoro-5-hydroxy-3-(N-3-pentyl-N-n-propylamino)chroman (180 mg,0.6 mmol) was dissolved in ether. HCl in ether was added to precipitatethe HCl-salt, and gave after drying 200 mg of(R)-8-fluoro-5-hydroxy-3-(N-3-pentyl-N-n-propylamino)chromanhydrochloride as a white powder. Mp: 80°-100° C. (sinters).

f)(R)-8-Fluoro-3-(N-3-pentyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychroman

To a stirred, cooled solution (-72° C.) of(R)-8-fluoro-5-hydroxy-3-(N-3-pentyl-N-n-propylamino)chroman (3.53 g,11.9 mmol), triethylamine (3.33 ml, 23.9 mmol) and DMAP (catalyticamount) in 95 ml dry CH₂ Cl₂, under nitrogen atmosphere and dryconditions, trifluoromethanesulfonic anhydride (3 ml, 17.8 mmol) in 5 mldry CH₂ Cl₂ was added during 25 min. The uncolered solution turns tolight yellow, and then to black. After 30 min. at -70° C. The solutionwas extracted with 100 ml H₂ O. The aqueous phase was extracted with 100ml CH₂ Cl₂. The combined organic layers gave after drying (MgSO₄) andevaporation a brown-yellow oil. The crude product was purified by flashchromatography on silica with a gradient of hexane-hexane:EtOAc, 9:1 andgave 3.69 g of(R)-8-fluoro-3-(N-3-pentyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychromanas an uncolored oil. [α]_(D) ²² -62° (c 1.02 in MeOH).

g)(R)-8-Fluoro-3-(N-3-pentyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychromanhydrochloride

(R)-8-Fluoro-3-(N-3-pentyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychroman(100 mg, 0.23 mmol) was dissolved in ether. HCl in ether was added toprecipitate the HCl-salt, and gave after drying 110 mg of(R)-8-fluoro-3-(N-3-pentyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychromanhydrochloride as a white powder. Mp. 45°-60° C. (sinters).

h)(R)-8-Fluoro-5-methyloxycarbonyl-3-(N-3-pentyl-N-n-propylamino)chroman

(R)-8-Fluoro-3-(N-3-pentyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychroman(1.04 g, 2.43 mmol), palladium(II)acetate (55 mg),1,2-bis(diphenylphosphino)propane (100 mg) was dissolved in 10 ml DMF.Triethylamine (0.75 ml, 5.38 mmol) and MeOH (1.0 ml, 24.6 mmol) wasadded under CO atm. via septa. The solution was stirred at +70° C. for18 hours, and thereafter evaporated to dryness. 100 ml 2M NH₃ and 100 mlEtOAc was added and the aqueous phase was extracted with 100 ml EtOAc.The combined organic layers was dried (MgSO₄) and evaporated. Flashchromatography on silica with a gradient of Hexane-Hexane:EtOAc, 50:1gave 0.76 g of(R)-8-fluoro-5-methyloxycarbonyl-3-(N-3-pentyl-N-n-propylamino)chromanas an uncoloured oil. Purity: 94% according to GC.

i) (R)-5-Carbamoyl-8-Fluoro-3-(N-3-pentyl-N-n-propylamino)chroman

(R)-8-Fluoro-5-Methyloxycarbonyl-3-(N-3-pentyl-N-n-propylamino)chroman(0.72 g, 2.13 mmol) was hydrolysed with KOH (0.20 g, 3.1 mmol) in 20 mlMeOH and 10 ml H₂ O, under reflux conditions for 20 hours and gave afterevaporation, and co-evaporation with toluene,(R)-8-fluoro-5-carboxy-3-(N-3-pentyl-N-n-propylamino)chroman as a whitesolid. SOCl₂ (0.8 ml, 11 mmol) was added to a slurry of(R)-8-fluoro-5-carboxy-3-(N-3-pentyl-N-n-propylamino)chroman in 50 mldry CH₂ Cl₂ and 1 drop DMF (catalytic amount). After reflux for 2 hours,the slurry was evaporated, and the residue, dissolved in 10 ml dry THFwas added dropwise to 35 ml ice-cooled conc. NH₃ under stirring. The THFwas evaporated after 2 hours and extraction with EtOAc×2, drying (Na₂SO₄) and evaporation gave 0.51 g of a crude product. Purification byflash chromatography with hexane:EtOAc:NH₃, (60:40:0.5) gave 0.41 g of(R)-5-carbamoyl-8-fluoro-3-(N-3-pentyl-N-n-propylamino)chroman as lightyellow crystals.

Recrystallisation was made from EtOAc/hexane. [α]_(D) ²² -103° (c 1.0 inMeOH), Mp: 111°-113° C.

Example 93 (R)-8-fluoro,3-(N-isopropyl,N-propylamino)5-carbamoylchromanhydrochloric acid

a) (R)-8-Fluoro-5-methoxycarbonyl-3-(N-isopropyl,N-propylamino)chroman

(R)-8-Fluoro-3-(N-isopropyl,N-propylamino)-5-trifluoromethanesulfonyloxychroman(2.4 g, 6.0 mmol), triethylamine (1.3 g, 12.9 mmol),1,3-bis(diphenylphosphino)propane (95 mg, catalytic amount),palladium(II)acetate (48 mg, catalytic amount) and DMF/MeOH (30 mL, 3:1)were mixed in a 50 mL three necked round bottom flask. The flask wasevacuated followed by the inlet of CO (repeated two times). The reactionmixture was stirred at 70° C. for 7.5 hours. The solvent was removed invacuo and the residue was dissolved in diethyl ether/sat: NaHCO₃. Thelayers were separated and the water phase was extracted once with ether.The combined ether layers were dried (MgSO₄) and the solvent was removedin vacuo to give a crude which was purified by flash chromatography(SiO₂, hexane/EtOAC, 9:1) to give 1.3 g of the title compound (71%yield).

b) (R)-8-fluoro, 3-(N-isopropyl,N-propylamino)5-carbamoylchromanhydrochloric acid

(R)-8-Fluoro-5-methoxycarbonyl-3-(N-isopropyl,N-propylamino)chroman (1.3g, 4.2 mmol) and KOH (0.52 g, 8.4 mmol) were mixed in methanol (6 mL)and refluxed for 2.5 hours. The solvent was removed in vacuo. Theresidue was dissolved in water and made acidic by the addition of 2MHCl. The solvent was removed in vacuo. The residue was dissolved inSOCl₂ (30 mL) and refluxed for 2.5 hours. The solvent was removed invacuo. The residue was dissolved in CH₂ Cl₂ and the solvent was removedin vacuo again (repeated three times in order to remove the excess ofSOCl₂. The residue was then dissolved in diethyl ether (50 mL). Thesolution was cooled to -30° C. before NH₃ (g) separated and thewater-phase was extracted with ether. The combined ether layers weredried (K₂ CO₃) and the solvent was removed in vacuo to give a crudewhich was purified by flash chromatography (SiO₂, EtOAc/hexane, 1:1) togive 1.0 g of the title compound (yield 80%). Recrystallization fromEtOAc/hexane gave crystals with Mp 139°-140° C. The resulting compoundis an 5-HT_(IA) antagonist.

A Preferred Embodiment

It has turned out that various compounds tested within the inventionshow a great variability in the three different parameters: selectivityfor 5-HT_(IA) receptors, agonist/antagonist functional effects in ratsand bioavailability after oral administration of the test compound. Ithas been difficult to identify compounds possessing all threeadvantageous properties. There is no guidance in the prior art how toobtain compounds with this combination of properties.

Surprisingly, it has been found that the racemic compound of theinvention,3-(N-isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman showsexcellent bioavailability, and possess a high affinity to a specificsubgroup of 5-hydroxytryptamine receptors in CNS, the 5-HT_(IA).

Furthermore, it has been found that high affinity for the 5-HT_(IA)-receptor in CNS is strictly stereospecific as regards the compound,3-(N-isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman. The(R)-enantiomer of3-(N-isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchromanpossesses a high affinity for 5-HT_(IA) receptors in CNS while the(S)-enantiomer of3-(N-isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman lacksactivity for 5-HT_(IA) receptors. The (R)-enantiomer of3-(N-isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman shows agood bioavailability, too. Thus, the racemate as well as the(R)-enantiomer of the compound of the invention can be used in thetreatment of 5-hydroxytryptamine mediated states and disorders inmammals including man.

The compound of this preferred embodiment of the present invention is3-(N-isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman asracemate and (R)-enantiomer having the formula ##STR18## in the form offree base or pharmaceutically acceptable salts thereof.

Both organic and inorganic acids can be employed to form non-toxicpharmaceutically acceptable acid addition salts of the compound of thisinvention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic,hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric,dibenzoyltartaric, diacetyltartaric, pamoic, ethanedisulfonic, sulfamic,succinic, propionic, glycollic, malic, gluconic, pyruvic, phenylacetic,4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic,4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxybenzoic,3-hydroxy-2-naphtoic, nicotinic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic,naphthalenesulfonic, ascorbinic, cyclohexylsulfamic, fumaric, maleic andbenzoic acids. These salts are readily prepared by methods known in theart.

Preparation

The (R)-enantiomer may be obtained according to known methods such asfrom racemic diastereomeric salts by means of fractional crystallisationor covalent diastereomers by means of chromatography. The enantiomericseparation may be performed before alkylation of the amino group (MethodA) or after N-alkylation (Method B). The scheme below illustrates theMethods A and B in more detail: ##STR19##

The compound V may be transferred to compound VI by using known methodsteps such as N-alkylation, demethylation and finally conversion to theleaving group Y.

The preparation of the racemic compound of the invention may start fromthe compound 5-methoxy-3-chromanone (prepared analogously to thedescription in EP 222 996) followed by known methods such as reductiveamination, N-alkylation, demethylation and finally conversion to theleaving group Y to obtain the racemate of compound VI.

The racemic form as well as the (R)-enantiomer of the compound of theinvention, may be prepared according to the following methods: ##STR20##i, converting the compound of formula VI ##STR21## wherein Y is aleaving group such as trifluoromethane sulfonate (OSO₂ CF₃), halide e.g.Cl, or Br or I by a catalytic cycle using a zerovalent transition metal(M) such as Pd or Ni, which may be generated in situ and undergoes anoxidative addition to the aryl-Y-bond. Treatment with carbon monoxidefollowed by amination with isopropylamine give the the compound offormula I, whereafter if desired it is converted to a salt.

ii, Alternatively, the compound of formula VI is converted to thecompound of formula VII ##STR22## wherein Z is Cl, Br, OH or OR_(p),where Rp is C₁ -C₆ alkyl, by catalytic cycle using a zerovalenttransition metal, with ability to undergo oxidative addition toaryl-Y-bonds e.g. The aryl-SO₃ CF₃ bonds. The aryl-CO-metal-Y complex isformed by treatment with carbon monoxide (CO).

Further reagents are an alcohol such as methanol, ethanol, a tertiaryamine base such as a trialkylamine e.g. triethylamine in an inertorganic solvent preferentially a polar aprotic solvent such asdimethylformamide (DMF), dimethylsulfoxide (DMSO), acetone, acetonitrileetc. The reaction is normally performed at a temperature between +40° to+120° C. and at a pressure between 100 to 500 KPa (iia). This isoptionally followed by hydrolysis and treatment with a thionyl halide,e.g. thionylchloride, to obtain the corresponding acid halidederivative.

The compound of formula VII is aminated (iib) with isopropylamine in anonpolar aprotic solvent e.g. toluene, benzene at reflux temperature orbetween 0° to 100° C. to give the compound of formula I.

Example 94 3-(N-Isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman

a) 3-Isopropylamino-5-methoxychroman hydrochloride

5-Methoxy-3-chromanone (16 g, 0,089 mol) and isopropylamine (6,4 g,0,112 mol) were reacted via reductive amination by known mehods (ClintonF. Lane Synthesis 1975 vol. 46 p. 135) to give the title compound. Mp.255° C.

b) 3-(N-Isopropyl-N-n-propylamino)-5-methoxychroman

A mixture of the product obtained in a) above (14 g, 0,06 mol),1-iodopropane (15 g, 0,08 mol), K₂ CO₃ and acetonitrile (250 ml) wasstirred under reflux for 4 days. After chromatography the desiredproduct was isolated as a colourless oil. GC-MS(CI-mode) M+1=264 (100%).

c) 3-(N-Isopropyl-N-n-propylamino)-5-hydroxychroman

The product from b) above (10 g, 0,038 mol) was demethylated using BBr₃in dichloromethane. GC-MS(CI-mode) M+1=250 (100%).

d) 3-(N-Isopropyl-N-n-propylamino)-5-trifluoromethanesulfonoxychroman

The product from c) above (10 g, 0,04 mol) was dissolved in CH₂ Cl₂ andcooled to -30° C. Pyridine (6 g, 0,076 mol) was added followed bytrifluoromethanesulfonic anhydride (14 g, 0,05 mol). The solution wasstirred at -20° C. for 3 hours and then allowed to reach ambienttemperature. The solution was washed with aqueous NaHCO₃, dried with Na₂SO₄ and evaporated to dryness. The oil was finally purified by flashchromatography (silica gel) by elution with ethyl acetate/hexane 1:9.GC-MS(CI-mode) M+1=382 (100%)

e) 3-(N-Isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman

A mixture of the product from d) above (3 g; 0.008 mL),1,3-bis(diphenylphosphine)propane (150 mg), palladium (II) acetate (75mg), and isopropylamine (5 ml) in 30 ml DMF was placed in a Parr glassvessel. CO at 2 bar was added and the mixture was shaken at 60° C. for 4hours. After work up and chromatographic purification the desiredcompound was obtained as white crystals with mp 124° C. (base).

Example 95(R)-3-(N-isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman (I)(Method A)

a) 3-Amino-5-methoxychroman hydrochloride (II)

3-Amino-5-methoxychroman was prepared according to known methods (ActaPharm. Suec. 24, 169-182, 1987). Mp: 237°-238° C.

b) (R)-3-Amino-5-methoxychroman (III)

The racemic 3-amino-5-methoxychroman as base (1.0 g; 5.5 mmol) andL(+)tartaric acid (1.0 g; 6.6 mmol) were dissolved in water (20 ml). Thesolution was heated to 70° C. and the clear solution was allowed tocrystallize at room temperature overnight. The precipitate was filteredoff giving 0.7 g of the tartrate salt with 99% optical purity of the(R)-isomer. Alkalization and extraction with CH₂ Cl₂ drying (Na₂ SO₄)and evaporation gave 0.35 g (35%) of the title compound as the freebase.

[α]_(D) ²⁵ =-20.8° (C=0.83, CH₂ Cl₂)

c) (R)-3-(N-Isopropylamino)-5-methoxychroman (V)

(R)-3-Amino-5-methoxychroman (1.0 g; 6 mmol) and acetone (2.5 g; 40mmol) were mixed with methanol (820 ml), acetic acid (0.4 g; 6.6 mmol)and NaCNBH₃ (1.2 g; 19 mmol), pH was adjusted to 6.0 with acetic acid.Stirring was continued at room temperature for 3 days. The mixture wasevaporated and the residue was made alkaline and extracted with CH₂ Cl₂.After drying (Na₂ SO₄) and evaporation the title compound as base wastransformed to the HCl-salt. Yield: 1.1 g (83%). Mp: 289° dec.

[α]_(D) ²⁵ =-29° (C=0.015; MeOH)

d) (R)-3-(N-Isopropyl-N-n-propylamino)-5-methoxychroman

(R)-3-(N-Isopropylamino)-5-methoxychroman (17.5 g, 0.079 mol) wasdissolved in dimethylformamide (DMF) (180 mL). K₂ CO₃ (21.8 g, 0.18 mol)and 1-iodopropane (53.8 g, 0.32 mol) were added. The reaction mixturewas then stirred at 50° C. for 5 days. The solvent was removed in vacuo.The residue was dissolved in ether/NH₃ (1M). The phases were separatedand the water phase was washed once with ether. The combinedether-layers were dried (MgSO₄) and the solvent was removed in vacuo togive a yellow oily residue. The oil was dissolved in dry ether and titlecompound was obtained in form of the HCl-salt in 66% yield (15.7 g) byslow addition of HCl in ether at 0° C. Mp (HCl-salt): 108°-120° C.

[α]_(D) ²⁵ =(Base)=-95.5° (C=0.1;MeOH)

e) (R)-5-Hydroxy-3-(N-isopropyl-N-n-propylamino)chroman

The HCl-salt of (R)-3-(N-isopropyl-N-n-propylamino)-5-methoxychroman(15.5 g, 52 mmol) was mixed with CH₂ Cl₂ (100 mL) under nitrogenatmosphere and cooled to -60° C. BBr₃ (27.2 g, 110 mmol) dissolved inCH₂ Cl₂ (50 mL), was added slowly. The temperature was then raised to 0°C. and the reaction mixture was stirred at 0° C. for 12 h. The reactionmixture was then slowly added to a stirred saturated NaHCO₃ solution.The layers were separated and the water layer was extracted once withCH₂ Cl₂. The combined organic layers were dried (MgSO₄). Removal of thesolvent in vacuo gave the phenolic title compound. Yield: 98%.

[α]_(D) ²² (Base)=-83.0° (C=0 1;MeOH) .Mp(HCl-salt): 215°-222° C.(decomposes).

f)(R)-3-(N-Isopropyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychroman(VI)

(R)-5-Hydroxy-3-(N-isopropyl-N-n-propylamino)chroman (13 g, 52 mmol) wasdissolved in CH₂ Cl₂ (100 mL) under nitrogen atmosphere. 2,4,6-Collidine(8.2 g, 68 mmol) was added and the mixture was cooled to -60° C.Trifluoromethanesulfonic anhydride (17.7 g, 62 mmol) was added slowlyover a one hour period. The temperature was then raised to 0° C. and thereaction was quenched with saturated Na₂ CO₃. The layers were separated.The water layer was pH adjusted with NH₃ (2M) to pH 8 and extracted oncewith CH₂ Cl₂. The combined organic layers were dried (MgSO₄). Removal ofsolvent in vacuo gave a brown oily residue which was purified by flashchromatography SiO₂ (CH₂ Cl₂)to give the triflate compound. Yield: 76%(15 g).

[α]_(D) ²² =-77.9° (C=0.01;MeOH)

g) (R)-3-(N-Isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman(I)

(R)-3-(N-isopropyl-N-n-propylamino)5-trifluoromethanesulfonyloxychroman(5.2 , g, 14 mmol) was dissolved in DMF (30 mL). isopropylamine (10 mL)was added and the vessel was evacuated followed by inlet of CO-gas. Thisprocedure was repeated twice before palladium (II) acetate (90 mg) and1,3-bis(diphenylphosphino)propane (144 mg) was added. The reactionmixture was then stirred for 10 h at 65° C. The solvent was removed invacuo. The dark brown residue was dissolved in diethylether/NH₃ (1M).The layers were separated and the water-phase was extracted once withether. The combined ether layers were dried (MgSO₄). Removal of solventin vacuo gave a yellow crystalline residue which was purified by flashchromatography SiO₂ (CH₂ CL₂ /EtOAc, 10:1). Recrystallisation from CH₂Cl₂ /hexane gave the pure amide(R)-3-(N-isopropylamino-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman.Yield: 35% (1.5 g).

[α]_(D) ²¹ =-87.0° (C=0.1;MeOH).Mp:94°-95.4° C.

Example 96(R)-3-(N-Isopropylamino-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman(I) (Method B)

a) (R)-3-(N-Isopropylamino)-5-methoxychroman (V)

5-Methoxy-3-chromanone (50 g, 0,28 mol; described in EP 0 222 996) wasdissolved in methanol (300 mL). The solution was cooled to 0° C. beforethe isopropylamine (70 mL, excess) was added. The pH was adjusted toabout 6 by the addition of acetic acid. NaCNBH₃ (12 g, 0.19 mol) wasadded in portions during a one hour period and pH was kept at pH 6. Theice-bath was removed and the mixture was stirred overnight at roomtemperature. The solvent was removed in vacuo. The residue was dissolvedin ether/NH₃ (1M). The layers were separated and the amine in the etherlayer was subjected to acid-base extraction (HCl(1M)/NH₃ (1M)). Dryingwith MgSO₄ and evaporation of solvent gave an colorless crystallineproduct.

Yield: 87% (54 g). Mp: 255°-56° C. (HCl-salt of the racemic product).

The racemic 3-(N-isopropylamino)-5-methoxychroman (IV; 54 g, 0.224 mol)was mixed with an equimolar amount of (+)-di-1,4-toluoyl-D-tartaric acid(98.6 g, 0.244 mol). The mixture was dissolved in boiling ethanol (170mL)/acetone (70 mL). The salt started to crystallize in the hot solventmixture but was not filtered off until the solvent had cooled down toroom temperature (20° C.). The salt was then recrystallized nine timesfrom ethanol/acetone (1:5) to give the pure diastereomeric salt. Yield:35% (54 g) (99% e.e). Mp: 166°-168° C. The free enantiomer as the base(R)-3-(N-isopropylamino)-5-methoxychroman was obtained by the extractionof the salt in ether/KOH (1M). Yield: 32%, 17.5 g,

[α]_(D) ²¹ =-32° (C=0.1;MeOH) Mp. 285°-286° C. (HCl-salt)

b) (R)-3-(N-Isopropyl-N-n-propylamino)-5-methoxychroman

The title compound was prepared in the same way as described in Example1b and obtained in the same amount and with the same physical data asgiven in Example 2d.

c) (R)-5-Hydroxy-3-(N-isopropyl-N-n-propylamino)chroman

The title compound was prepared in the same way as described in Example2e and obtained in the same amount and with the same physical data asgiven in Example 2e.

d)(R)-3-(N-Isopropyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychroman(VI)

The title compound was prepared in the same way as described in Example2f and obtained in the same amount and with the same physical data asgiven in Example 2f.

e) (R)-3-(3-N-Isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman(I)

The title compound was prepared in the same way as described in Example2 g and obtained in the same amount and with the same physical data asgiven in Example 2g.

Example 97

a) (R)-3-(N-Isopropyl,N-n-propylamino)-5-methoxycarbonylchroman

(R)-3-(N-Isopropyl,N-n-propylamino)-5-trifluoromethanesulfonyloxychroman(4.0 g, 10.5 mmol), triethylamine (2.3 g, 23.1 mmol) and a mixture ofDMF/MeOH (18 mL, 6:2) was mixed in a three necked round-bottom flask.The flask was evacuated followed by inlet of CO-gas (repeated twotimes). Finally 1,3-bis(diphenylphosphino)propane (0.11 g) andpalladium(II)acetate (0.07 g) was added. The mixture was stirred at 70°C. for 17 hours. The reaction mixture was diluted with diethyl ether,washed with 2M NH₃ and dried (MgSO₄). Removal of solvent in vacuo gave abrown oily residue which was purified by flash chromatography (SiO₂, CH₂Cl₂ /EtOAc; 10:1) to give the title compound in 82% yield (2.5 g).

[α]_(D) ²¹ =-131.6° (MeOH, 0.1M). GC-MS(70 eV)=291(M⁺), 262(100%)

b) (R)-3-(N-Isopropyl,N-n-propylamino)-5-N-isopropyl)carbamoylchroman(I)

(R)-3-N-(N-isopropyl,N-n-propylamino)-5-methoxycarbonylchroman (0.46 g,1.6 mmol), dissolved in MeOH (10 mL), was mixed with a solution of NaOH(0.06 g, 1.6 mmol) in water (3 mL). The reaction mixture was thenrefluxed for 3.5 hours before the solvent was removed in vacuo. Theresidue was dissolved in toluene. The toluene was removed in vacuo(repeated two times) in order to form an azeotrope to remove the water.The residue was then dissolved in SOCl₂ (5 mL) and refluxed for 1 hour.The excess of SOCl₂ was removed in vacuo. The residue was dissolved inCH₂ Cl₂ (20 mL, dried with molecular sieves 3 Å) before 4 mLisopropylamine was added. The reaction mixture was stirred for 1 hour atroom temperature (21° C.) before it was diluted with diethyl ether,washed (2M NH₃) and dried (MgSO₄). Removal of solvent in vacuo gave ayellow oily residue which was purified by flash chromatography (SiO₂,CH₂ Cl₂ /EtOAc; 5:2) to give the pure title compound in 88% yield (0.46g).

[α]_(D) ²¹ =-90.4° (MeOH 0.1) Mp:93°-94° C.

I claim:
 1. A process for preparing (R)-3-amino-5-methoxychroman whichcomprises the steps of:(i) dissolving racemic 3-amino-5-methoxychromanand L(+)tartaric acid in water to form the tartrate salt; (ii) heatingthe solution until a clear solution is obtained; and (iii) crystallizingthe tartrate salt by allowing the solution to cool to room temperature.